PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

Quinnetal. acta neuropathol commun (2020) 8:189 https://doi.org/10.1186/s40478-020-01062-w REVIEW PINK1/PARKIN signalling inneurodegeneration andneuroinflammation Peter M. J. Quinn1,2, Paula I. Moreira3,4,5, António Francisco Ambrósio4,6,7,8 and C. Henrique Alves4,6,7,8* Abstract Mutations in the PTEN-induced kinase 1 (PINK1) and Parkin RBR E3 ubiquitin-protein ligase (PARKIN) genes are associated with familial forms of Parkinson’s disease (PD). PINK1, a protein kinase, and PARKIN, an E3 ubiquitin ligase, control the specific elimination of dysfunctional or superfluous mitochondria, thus fine-tuning mitochondrial network and preserving energy metabolism. PINK1 regulates PARKIN translocation in impaired mitochondria and drives their removal via selective autophagy, a process known as mitophagy. As knowledge obtained using different PINK1 and PARKIN transgenic animal models is being gathered, growing evidence supports the contribution of mitophagy impairment to several human pathologies, including PD and Alzheimer’s diseases (AD). Therefore, therapeutic interventions aiming to modulate PINK1/PARKIN signalling might have the potential to treat these diseases. In this review, we will start by discussing how the interplay of PINK1 and PARKIN signalling helps mediate mitochondrial physiology. We will continue by debating the role of mitochondrial dysfunction in disorders such as amyotrophic lateral sclerosis, Alzheimer’s, Huntington’s and Parkinson’s diseases, as well as eye diseases such as age-related macular degeneration and glaucoma, and the causative factors leading to PINK1/PARKIN-mediated neurodegeneration and neuroinflammation. Finally, we will discuss PINK1/PARKIN gene augmentation possibilities with a particular focus on AD, PD and glaucoma. Keywords: PINK1, PARKIN, Mitophagy, Neurodegeneration, Alzheimer’s disease, Parkinson’s disease © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Background Mitochondria, first discovered in the late 19th century, are considered key for cellular bioenergetics [1, 2]. They consist of a double membrane with an intermembrane space. The inner membrane forms folds called cristae which provide an increased surface area for chemical and redox reactions to take place [3–5]. Mitochondria produce the majority of cellular adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). The protein complexes (cI-IV) of the respiratory chain transfer electrons from NADH and FADH2 (provided by the Krebs cycle) to molecular O2, a process also known as the electron transport chain (ETC). The ETC creates a membrane potential (ΔΨm) across the mitochondrial inner membrane by pumping protons from the mitochondrial matrix to the intermembrane space, thus creating a high concentration of protons in the intermembrane space and a low concentration in the mitochondrial matrix. Subsequently, along this chemiosmotic gradient, the protons move back into the mitochondrial matrix, via ATP synthase (cV). ATP synthase uses this process to create ATP from adenosine diphosphate (ADP) and inorganic phosphate (Pi) [6–9]. Previously thought to be only the “powerhouse” of the cell it is now clear that mitochondria are multifaceted. In addition to their role in cellular bioenergetics, mitochondria control reactive oxygen species (ROS) levels and calcium homeostasis, and biosynthesize macromolecules including lipids, amino acids and nucleotides [10]. Furthermore, mitochondria are involved in many cellular Open Access *Correspondence: [email protected] 6 Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal Full list of author information is available at the end of the article Page 2 of 20 Quinnetal. acta neuropathol commun (2020) 8:189 physiological processes, including cell fate, differentiation, proliferation and apoptosis [11, 12]. Alongside its more established roles, mitochondria are key regulators of the innate and adaptive immune system. Immune cells undergo significant cell-type specific metabolic changes during an immune response, moving from a quiescent to an active state that requires significant metabolites from mitochondria [13, 14]. Mitochondria can regulate immunity via metabolic pathways, inducing transcriptional changes, activating inflammation, mitochondrial dynamics (fission and fusion) and endoplasmic reticulum signalling [14, 15]. Mitochondrial stress, either driven by the environment, pathogenesis or ageing, leads to a myriad of dysregulation that can cause both neurodegeneration and neuroinflammation. Mitochondria are vital in regulating cellular adaption to stressors, including impaired biogenesis, mitochondrial DNA (mtDNA) damage, ageing, nutrient restriction and aberrant imbalances between fission and fusion events. If left unchecked, these processes can cause damage to nucleic acids, lipids and proteins through ROS, resulting in sustained oxidative stress [16, 17]. Oxidative stress modulates mitochondrial dynamics through posttranscriptional modifications, including ubiquitination [18]. This, in turn, leads to a build-up of damaged mitochondria and ultimately causes cell death and broader tissue dysfunction. In particular, tissues with high energy demands such as the heart, muscles, brain and retina are susceptible to mitochondrial dysfunction [19]. To mitigate the effects of stressors, several control mechanisms can be activated contributing to mitochondrial homeostasis [17]. Mitochondria first-line defence mechanisms including enzymatic (such as superoxide dismutase, the peroxiredoxin/thioredoxin system and the glutathione peroxidase/reductase system) and non-enzymatic (such as GSH, vitamins E, A and C) antioxidants contribute to the maintenance of redox homeostasis [20]. However, beyond the utilization of antioxidants there exists several mitochondrial quality control mechanisms. These include regulation of mitochondrial fission and fusion events, which facilitate segregation of damaged mitochondria and axonal transport of mitochondria (fission) and the exchange of materials needed for their repair, such as mtDNA (fusion) [16, 21]. The mitochondrial unfolded protein response system, a mitochondria-to-nucleus transduction pathway, which promotes mitochondrial and cellular function if mitochondrial damage is sensed [22]. The ubiquitin–proteasome system leads to degradation of damaged outer mitochondrial membrane (OMM) proteins, and proteases lead to the removal of inner mitochondrial membrane (IMM) and mitochondrial matrix proteins [23]. Lastly, the export of damaged proteins via mitochondrial-derived vesicles (MDVs) or selective removal of damaged mitochondria via mitophagy end with their degradation in lysosomes [24]. PTEN-induced kinase 1 (PINK1) and Parkin RBR E3 ubiquitin-protein ligase (PARKIN) signalling play a key role in mitophagy and mitochondrial motility and size. PINK1 accumulates at the OMM in response to a reduction in mitochondrial ΔΨm caused by damage/dysfunction. In turn, this recruits PARKIN from the cytosol to the OMM were its E3 activity promotes mitophagy, through ubiquitination of mitochondrial proteins, leading to mitochondrial degradation. Defective mitophagy and PINK1/PARKIN signalling are present in neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD) and glaucoma [25–30]. Mutations in the PINK1/PARKIN signalling pathway disrupts the sensitive homeostatic and quality control processes conducted by mitochondria. Mutations in PINK1 and PARKIN are localised throughout their genes affecting all their protein domains (Fig.1). PINK1 and PARKIN mutations are responsible for more than 50% of the autosomal recessive juvenile parkinsonism (ARJP) cases [31]. However, there are several other causative genes for PD linked to mitochondrial dysregulation, including LRRK2, DJ1, ATP13A2 and SCNA, in addition to other PD risk genes [32–45]. Furthermore, dysregulation of PINK1/PARKIN signalling has been associated with amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD), as well as eye diseases, such as agerelated macular degeneration (AMD), and is associated with retinal degeneration [46–51]. Efforts for the amelioration of mitochondrial dysfunction through lentiviral and adeno-associated viral (AAV) mediated PINK1 and PARKIN gene augmentation therapeutics show promise (Table1). Main text PINK1/PARKIN signalling The mitochondrial serine/threonine-protein kinase PINK1, also known as BRPK and PARK6, protects cells from mitochondrial stress-induced dysfunction. Localized to chromosome 1 in position 1p36.12, the PINK1 gene has 8 exons encoding a 581 amino acid protein. It contains an N-terminal mitochondrial targeting sequence (MTS), a transmembrane domain (TM), a N-terminal regulatory domain (NT), a conserved protein kinase domain comprising of a N-lobe and C-lobe, and lastly a C-terminal domain (CTD) (Fig.1a). PARKIN, also known as PDJ, AR-JP, LPRS2 and PARK2 is localized to chromosome 6 in position 6q26 [61, 62]. PARKIN gene has 14 exons encoding a 465 amino acid protein which is comprised of an N-terminal ubiquitin-like (Ubl) domain and a C-terminal RING1-IBR-RING2 (RBR) domain. Page 3 of 20 Quinnetal. acta neuropathol commun (2020) 8:189 A RING0 domain sits N-terminally adjacent to RING1 and residing between the in-between-RING (IBR), and RING2 domains is a Repressor Element of Parkin (REP) motif (Fig.1b) [63–66]. Under healthy conditions, mitochondria have an optimal, relatively high ΔΨm and will import, process and lead to the degradation of PINK1 (Fig.2). However, under unhealthy conditions like oxidative stress, low ΔΨm causes PINK1 mitochondrial accumulation leading to PARKIN recruitment from the cytoplasm and initiation of autophagic degradation of the damaged mitochondria, the mitophagy pathway (Fig.3) [67–70]. This pathway is governed by phosphorylation and ubiquitination, posttranscriptional modifications mediated by PINK1 and PARKIN, respectively. The tightly regulated import to and subsequent proteolysis of PINK1 in the mitochondria leads to its processing from the full length 63kDa protein precursor to the mitochondrial processing peptidase (MPP)-processed 60 kDa intermediated, to its final presenilins-associated rhomboid-like protein (PARL)-processed 52 kDa “mature” form (Fig. 2a, b) [71–73]. The translocase of the outer membrane (TOM) and of the inner membrane Fig. 1 Schematic representations of PINK1 and PARKIN domains and disease-related mutations. a PINK1 is composed by 581 amino acids, encompassing the mitochondrial targeting sequence (MTS), transmembrane region (TM), N-terminal regulatory region (NT), N-lobe of the kinase domain, C-lobe of the kinase domain and the C-terminal domain (CTD). Mitochondrial processing peptidase (MPP) and presenilin-associated rhomboid-like (PARL) cleavage sites and PINK1 auto-phosphorylation sites are depicted in the figure (S228, T257, S402). b PARKIN is formed by 465 amino acids with a ubiquitin-like domain (UBL), linker, really-interesting-new-gene (RING)/unique Parkin domain (R0/UPD), RING1 (R1), in-between-RING (IBR), repressor element of Parkin (REP), and a RING2 (R2) domain. E2 co-enzyme and p-Ser65-Ub binding sites, as well as Ser65 phosphorylation and Cys431 catalytic sites, are displayed. Disease-associated mutations collected from the movement disorder society genetic mutation (www.mdsge ne.org/) and ClinVAR (www.ncbi.nlm.nih.gov/clinv ar/) databases are displayed on top of schematic representation. In red are depicted the mutations considered pathogenic Page 4 of 20 Quinnetal. acta neuropathol commun (2020) 8:189 (TIM)23 complexes facilitate the importation of the PINK1 precursor via interaction with its MTS to the IMM. At the IMM, PINK1 undergoes cleavage at Ala103 by the protease PARL in a ΔΨm dependent manner. Under normal, healthy conditions PINK1 is imported and processed for degradation. In contrast, if ΔΨm dissipates, PINK1 remains localized to the OMM and is unable to be processed by PARL [72, 74]. Upon cleavage, PINK1 returns to the cytosol to be degraded by the ubiquitin–proteasome system by UBR1, UBR2 and UBR4 through the N-end rule pathway, leading to low levels of PINK1 (Fig.2a, b) [75]. Recently Sekine etal. [76] found some PD related PINK1 mutations, I111S, C125G and Q126P, affecting an evolutionary conserved negatively charged amino acid cluster motif that constitutes the C-terminal of the PINK1 TM, can still be imported even Table 1 Summary ofthePARKIN andPINK1 gene augmentation viral vectors AAV Adeno-associated virus, CBA hybrid cytomegalovirus immediate/early enhancer-chicken β-actin, CMV cytomegalovirus, PGK phosphoglycerate kinase, S.N. substantia nigra, TU transducing units, Vg viral genomes, VSVG vesicular stomatitis virus Viruses Capsid serotype Promoter Sequence Injection place Volume injected Dose Disease model Animal References Lentivirus HIV-1 based vector with VSVG envelops PGK Rat Parkin S.N. 2.5 µl 3.6 × 108 pg of p24 per ml α-synuclein rat model for PD Wistar rats [52] Lentivirus HIV-1 based vector with VSVG envelops CMV Human PARKIN S.N. 2 µl 108 pg of p24 per ml 6-Hydroxydopamine rat model for PD Rats [53] AAV 2/2 CBA HA-taggedPARKIN S.N. 2 µl 3.6 × 1012 vg/ ml MPTP-treated mice, a model for sporadic PD C57BL/6 mice [54] AAV 2/2 and 2/5 CMV/CBA Human PARKIN S.N. 2 × 2 µl 2.6 × 1012 vg/ ml 6-Hydroxydopamine rat model for PD Rats [55] AAV 2/2 CMV/CBA Human PARKIN S.N. 4 µl 5 × 1012 vg/ml Tau-induced dopaminergic degeneration rat model for PD Sprague– Dawley rats [56] AAV 2/6 PGK Rat Parkin S.N. 2 µl 4.7 × 1010 TUs/ml Methamphetamine induced neurotoxicity rat model for PD Sprague– Dawley rats [57] AAV 2/8 CMV Human PARKIN S.N. 2 µl in mice 3 µl in rats 2.0 × 1011 vg/ ml T240R-PARKIN induced dopaminergic degeneration model for PD C57BL/6 J mice Wistar rats [58] AAV 2/2 CMV Rat Parkin Vitreous 5 µl 1.0 × 1013 vg/ ml Chronic hypertensive glaucoma model Sprague– Dawley rats [30] AAV 2/1 CMV Human PARKIN Striatum 3 µl in rats 5 × 10 µl in monkeys 7.0 × 1012 vg/ ml α-synuclein rat model for PD Sprague– Dawley rats Macaque monkeys [59] AAV 2/2 CMV Human PINK1 Hippocampus 2 µl 5.0 × 1012 vg/ ml mAPP mouse model for AD mice [60] Page 5 of 20 Quinnetal. acta neuropathol commun (2020) 8:189 if ΔΨm dissipates. These mutants were found not to be cleaved by PARL but by the protease OMA1 at the IMM, suggesting that PINK1 did not accumulate on the damaged mitochondria’s OMM for initiation of mitophagy. However, these PINK1 mutants could lead to PARKIN recruitment under OMA1 suppression. In contradiction to the degradation of the 52 kDa PINK1 by the N-end rule pathway is the finding by the Przedborski Lab that ubiquitinated PINK1 is mostly anchored to the OMM and not in the cytosol. Importantly, they identified that the N-terminal phenylalanine forming a proposed N-degron motif of PINK1 was not facing the cytosol but rather located inside the OMM, suggesting PINK1’s low mitochondrial levels are due to continuous ubiquitination and proteasomal degradation under healthy conditions [73]. Recently, the same team identified the mechanism by which PINK1 content is kept at low levels. They found that upon PARL-processing the 52kDa PINK1 localizes at the mitochondrialendoplasmic reticulum interface and can interact with ER-associated degradation pathway E3 ligases Gp78 and HRD1 (Fig.2c). These facilitate PINK1’s ubiquitination allowing valosin containing proteins, UFD1 and UFD2A, to target PINK1 for proteasomal degradation [77]. Other proteases such as matrix-AAA and caseinolytic mitochondrial matrix peptidase (ClpXP) can cleave PINK1. These may coordinate with PARL to govern the stability and localization of PINK1 [71, 75]. In damaged mitochondria, TOM does not import PINK1, and it remains uncleaved at the OMM, where it undergoes dimerization and autophosphorylation (Fig.3) [78, 79]. Interestingly, Sekine etal. [76] found that without the TOM complex Fig. 2 The canonical PINK1/PARKIN pathway. a and b In healthy mitochondria, PINK1 is constitutively imported via translocase of the outer membrane (TOM)/translocase of the inner membrane (TIM)23 complexes to the inner mitochondrial membrane (IMM), cleaved by two proteases (mitochondrial processing peptidase (MPP) and presenilin-associated rhomboid-like (PARL)) and retro-translocated to the cytosol. Cleaved PINK1 is then degraded by the ubiquitin/proteasome system. While Parkin remains inactive in the cytosol. (a and c) PINK1 is also present at the mitochondria-endoplasmic reticulum (ER) interface, where it interacts with the endoplasmic-reticulum-associated protein degradation (ERAD) machinery. At the ER, PINK1 degradation by the proteasome is controlled by the ERAD E3 ubiquitin ligases HRD1 and gp78 and by the ERAD-associated proteins VCP, UFD1, andUFD2A Page 6 of 20 Quinnetal. acta neuropathol commun (2020) 8:189 accessory member Tom7 PINK1 was imported to depolarised mitochondria. Tom7 appears crucial in PINK1 OMM accumulation and also plays a role in PINK1 kinase activation for PARKIN recruitment. Phosphoglycerate mutase family member 5 (PGAM5) also binds PINK1 and is required for mitochondrial stabilisation of full-length PINK1 on the OMM upon mitochondrial depolarisation, preventing its cleavage by PARL at the IMM [80]. Under basal conditions, three factors have been identified which show that PARKIN’s protein-folding maintains PARKIN in an autoinhibited state: (1) inaccessibility of the E2-binding site on RING1 due to its occlusion by the REP domain [65]; (2) a conserved cysteine residue on RING2 (Cys431) is made inaccessible by RING0 [64, 65, 81]; (3) the Ubl domain inhibits parkin activity through the interface with RING1 and IBR domains [82–85]. The protein folding of PARKIN thus prevents the binding of Ub containing E2s to RING1 and the subsequent thiolbased transfer of Ub to the RING2 cysteine residue. The Cys431 residue is catalytic, being required for the ligase activity of PARKIN. The catalytic residue allows for the formation of an isopeptide bond between Ub and the lysine residue of the protein [64, 65, 86]. PINK1 is upstream of PARKIN and through the Ub/ Ubl switch leads to activation of PARKIN by their phosphorylation at residue Ser65 (Fig.3) [83, 84, 87–93]. Phosphorylation of Ubl increases PARKIN’s affinity for pUb. The binding of pUb to PARKIN enhances the rate at which PARKIN itself is phosphorylated by PINK1 [94, 95]. Specific phosphorylation of either Ub or Ubl leads to PARKIN activation; concomitant phosphorylation, however, leads to enhanced PARKIN activation [91, 92, 94]. Binding of pUb to PARKIN’s Ubl domain is essential for remodelling of and exposure of RING1 to the binding of the Ub containing E2s and is in line with previous computational analysis [83, 96, 97]. Ubl phosphorylation or binding of pUb to Ubl has also been shown to lead to local rearrangement of the IBR and its decreased affinity for the Ubl domain, revealing cryptic binding sites in a region called the Ubiquitin Binding Region (UBR) [85]. Three surface areas, UBR1, 2 and 3, that could interact with Ub were explored. Both UBR2 and UBR3 were needed for PARKIN activity. The IBR rearrangement in active PARKIN allows binding of Ub containing E2s to the binding site on RING1 while its Ub creates a bridge to the IBR of a neighbouring PARKIN molecule [85]. This association allows for the utilization of the RING2 catalytic domain of neighbouring PARKIN molecules [85]. In summary, pUb is important for dissociation and phosphorylation of PARKIN’s Ubl domain allowing its recruitment to the mitochondria. Subsequent PINK1 activation of PARKIN through Ser65 phosphorylation in the Ubl facilitates binding of E2 enzymes leading to PARKIN’s ligase activity. Several mutations exist throughout PARKIN, affecting its activity and stability (Fig.1b) [98–100]. If there is severe mitochondrial dysfunction the amplified phospho-ubiquitin chains on the OMM signal the recruitment of autophagy adaptors such as nuclear dot Fig. 3 PINK1/PARKIN-directed quality control in damaged mitochondria. After damage, PINK1 is no longer imported into the inner mitochondrial membrane (IMM) and accumulates on the outer mitochondrial membrane (OMM). Here, a supercomplex composed by TOM complex subunits and PINK1 homodimers is formed, facilitating PINK1 autophosphorylation and activation. Once activated, PINK1 phosphorylates ubiquitinated substrates on the OMM and PARKIN enable its E3 ubiquitin ligase functions in concert with E2 ubiquitin-conjugating enzymes. PINK1-mediated phosphorylation of ubiquitin phospho-Ser65ubiquitin on OMM substrates acts as the PARKIN receptor for its recruitment from the cytosol. PINK1 and PARKIN initiate a positive feedback loop, resulting in the coating of damaged mitochondria with phospho-ubiquitin chains. Individual OMM proteins decorated with poly-ubiquitin can be extracted from the membrane and degraded by the 26 S proteasome. Phospho-ubiquitin chains are bound by two mitophagy adaptors, nuclear domain 10 protein 52 (NDP52) and optineurin. Phosphorylation of optineurin by TANK Binding Kinase 1 (TBK1) enhances its binding to ubiquitin chains and promotes selective autophagy of damaged mitochondria. The two adaptors recruit autophagosomes via microtubule-associated protein 1A/1B-light chain 3 (LC3) binding, allowing the engulfment of dysfunctional mitochondria resulting in their direct degradation in lysosome Page 7 of 20 Quinnetal. acta neuropathol commun (2020) 8:189 protein 52 (NDP52) and Optineurin (OPTN). In turn, NDP52 and OPTN lead to the recruitment and activation of tank binding kinase 1 (TBK1), activated TBK1 phosphorylates OPTN stabilizing its binding at the phospho-ubiquitin chains [101]. Interestingly, PINK1/ PARKIN-dependent mitophagy-induced sequestration of TBK1 leads to its removal from its physiological role at the centrosome causing G2/M cell cycle arrest. This highlights a possible role of PINK1/PARKINs in mitochondrial quality control before cell division takes place, preventing “unfit” mitochondria being passed on to daughter cells [102]. OPTN and NDP52 along with other autophagy adaptors lead to the recruitment of microtubule-associated proteins 1A/1B light chain 3 (LC3), which engage with the autophagosome. Migration and subsequent fusion of the autophagosome with the lysosome, which is modulated by the RAS-related GTP-binding (Rab) proteins, creates the autolysosome where the mitochondrial proteins are degraded and processed for recycling (Fig.3). Initiation of autophagy has been found in the absence of LC3 via the Unc-51 like kinase 1 (ULK1) complex, which is comprised of ULK1, FAK family kinase-interacting protein of 200kDa (FIP200), autophagy related gene (ATG)12 and ATG101 [103]. The ULK1 complex, which mediates autophagy in a nutrient-dependent manner, is recruited to ubiquinated cargo independently of AMPK by the cooperation of NDP52, and TBK1 [103]. Recently, Nozawa etal. [104] found that TBC1 domain family member 9 (TBC1D9), which is recruited to mitochondria via Ca2+-dependent Ub-binding, is essential for the activation and recruitment of TBK1 and therefore the subsequent recruitment of NDP52 and the ULK1 complex to damaged mitochondria. PINK1/PARKIN inneurodegeneration Neurodegeneration corresponds to any pathological conditions, primarily affecting neurons [105]. Typically, neurodegenerative diseases are progressive disorders that lead to neuronal degeneration and cell death. The umbrella term “neurodegenerative diseases” includes conditions such as AD, PD, amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD) and also eye diseases, such as age-related macular degeneration (AMD), glaucoma and a subset of inherited retinal dystrophies. Ageing is considered a primary risk factor in most neurodegenerative diseases [106]. Mitophagy increases in muscles and neurons during ageing but disruption of PINK1/ PARKIN signalling abolishes this increase, hindering this crucial quality control mechanism and thus allowing the accumulation of harmful mitochondria [107– 111]. Imbalances in mitochondrial fission and fusion are important for neuronal dynamics and are affected in neurodegeneration being linked to programmed cell death pathways [112]. PINK1 and PARKIN are essential in these processes interacting with fission/fusion machinery molecules such as fission protein Drp1 (dynaminrelated protein 1) and fusion protein OPA1 (optical atrophy 1). Overexpression of Pink1 or Parkin in rat hippocampal neurons leads to increased fission and can suppress a mitochondrial elongation phenotype caused by Drp1 knockdown. A similar phenotype is caused by PINK1 inactivation, leading to increased fusion. Yu etal. [113] found that in dopaminergic neurons, similarly to hippocampal neurons, PINK1/PARKIN had a comparable influence on mitochondrial dynamics with tipping the fission/fusion balance towards more fission. Alzheimer’s disease, the most common cause of dementia in the elderly, is a progressive neurodegenerative disease leading to memory deficits and cognitive decline, which in turn lead to behavioural and speech impairments. Ageing is the predominant risk factor with a prevalence of 10% for individuals over the age of 65 [114]. Pathologically, AD is hallmarked by the presence of amyloid plaques, mainly consisting of agglomerated amyloid-β (Aβ) peptides, and neurofibrillary tangles, mostly consisting of hyperphosphorylated tau, which are associated to cellular degeneration [115]. Another prominent hallmark of AD is the accumulation of dysfunctional mitochondria [116]. Robust induction of PARKIN-mediated mitophagy is found in human patients’ brains and in a human amyloid precursor protein (hAPP) transgenic mouse model of AD [28]. During disease progression, cytosolic PARKIN levels are reduced, leading to increased mitochondrial dysfunction [28]. Mitochondria from AD patients skin fibroblasts exhibited slower recovery of ΔΨm after insult [27]. Dysregulated protein levels of PARKIN and PINK1 were found in AD fibroblasts and brain biopsies. In both AD fibroblasts and hippocampal brain biopsies from Braak II-III stage patients, full length and cleaved PINK1 were increased. However, while PARKIN was diminished in the AD fibroblasts, it was found upregulated in Braak VI stage hippocampal brain biopsies. In AD fibroblasts, PARKIN recruitment after mitochondria depolarisation was found to be reduced, indicating defective mitophagy due to insufficient tagging of damaged mitochondria. Overexpression of PARKIN could compensate for the defective mitophagy in the AD fibroblasts [27]. Familial cases of AD are linked to autosomal dominant mutations of presenilin 1 (PSEN1). Both PSEN1 and PSEN2 are involved in a molecular cascade that modulates mitophagy via their control of PINK1 transcription and function. Goiran etal. found that PARKIN upregulates PSEN1 promoter activation. In turn, control of γ-secretase activity, by PSEN1, targets APP leading to its fragmentation, yielding Aβ and the APP Page 8 of 20 Quinnetal. acta neuropathol commun (2020) 8:189 intracellular domain (AICD). Interaction of forkhead box O3a (FOXO3a) with AICD initiates Pink1 transcription and AICD-mediated control of autophagic processes, which were found to be PINK1 dependent. As PINK1 recruits PARKIN to damaged mitochondria this highlights a feedback loop between the two genes that may become disrupted in neurodegenerative conditions [117, 118]. Parkinson’s disease is a movement disorder attributed to the loss of dopaminergic neurons in the substantia nigra. Motor symptoms include resting tremor, rigidity and bradykinesias, while non-motor symptoms include autonomic dysfunction, anxiety and sleeping problems. PINK1 and PARKIN are mutated in some forms of familial PD [119, 120]. Pink1 and Parkin null Drosophila have learning and memory abnormalities and weakened circadian rhythms, in addition to underlying electrophysiological irregularities in clock neurons [121]. Late-stage PD patients can develop dementia with an accumulation of α-synuclein in Lewy bodies [41, 59, 122, 123]. Nitrosative stress is a key pathological hallmark in PD and aging. Nitric oxide-induced S-nitrosylation of PARKIN and PINK1 leads to compromised mitophagy and thus accumulation of damaged mitochondria [124–126]. One of the major causes of early-onset PD is due to loss-offunction mutations in genes including glucocerebrosidase (GBA), RAB39B, DJ-1, PINK1 and PARKIN [25, 26, 127–130]. Pink1 and Parkin KO mice show minimal signs of neurodegeneration but still provide valuable insights into possible mechanisms of action [131–135]. Parkin KO mice have an increase in extracellular dopamine concentration in the striatum, there is reduction in synaptic excitability in spiny neurons and dysfunction of the nigrostriatal pathway [131]. Another mouse model, presenting inactivated PARKIN due to a exon 3 deletion causing a premature stop codon, showed cognitive and motor deficits with inhibition of both amphetamineinduced dopamine release and glutamate neurotransmission [133]. Additionally, some mouse and rat Parkin KO models exhibit no neurodegeneration or any detectable neurochemical or pathological changes compared to wild type counterparts [135, 136]. This may be due to developmental compensation for PARKIN in these models. Due to the lack of neurodegeneration found in mouse KO Parkin models, Stephenson etal. [137] tried a novel approach by creating a double KO of Parkin and Parkin co-regulated gene (PACRG). Parkin and PACRG share a bidirectional promoter, with the transcriptional start sites being approximately 200bp apart. However, no abnormalities of the dopaminergic system in the substantia nigra and no loss of neurons were found. Analysis of PARKIN and its substrates has yielded possible PD associated neurodegenerative mechanisms. PARKIN mediates the ubiquitination and proteasomedependent degradation of synaptotagmin-11 (Syt11) under normal conditions [138]. Syt11 is a novel risk gene involved in PD whose accumulation in dopaminergic neurons due to PARKIN dysfunction inhibits endocytosis and hence dopamine release leading to neurotoxicity [40, 138]. Interestingly, Wang etal. [138] found that knockdown of Syt11 in Parkin knockdown background lead to the recovery of the dopamine release in the substantia nigra. PARKIN also mediates the ubiquitination and proteasome-dependent degradation of Zinc finger protein 746 (ZNF746, also known as PARIS) under normal conditions [139]. Accumulation of ZNF76 occurs due to PARKIN inactivation and is present in PD human brain samples [139, 140]. ZNF746 is a transcriptional repressor of peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator-1α (PGC-1α) expression and its target gene nuclear respiratory factor 1 (NRF-1). In Parkin KO animals, dopaminergic neurons loss was found to be in a ZNF746-dependent manner with its overexpression leading to dopaminergic neuronal loss in the substantia nigra [139]. Recently, Brahmachari et al. [140] found that ZNF746 is a pivotal mediator of α-synuclein induced neurodegeneration affecting both dopaminergic and non-dopaminergic neurons. In α-synuclein overexpression mouse models c-Abl kinase phosphorylation of PARKIN led to the impairment of its activity and subsequent accumulation of ZNF746. Importantly, they found that ablation of ZNF746 leads to the rescue of the neurodegenerative phenotype observed in α-synuclein models of familial and sporadic PD [140]. PARKIN inactivation also leads to the accumulation of another one of its substrates, aminoacyl-tRNA synthetase complex interacting multifunctional protein-2 (AIMP2), found to be increased in Parkin KO mouse models and PD brain samples [140–143]. AIMP2 overexpression causes a progressive and degenerative loss of dopaminergic neurons due to Poly(ADP-ribose) polymerase-1 (PARP1) over activation. PARP1 inhibition in the AIMP2 overexpressed mouse model was protective and prevented degeneration of dopaminergic neurons [141]. Outside its role as an E3 ubiquitin ligase involved in mitophagy, PARKIN also has a role in transcriptional regulation (reviewed by Costa etal. [144]). As an example, PARKIN has been found to undergo nuclear translocation upon DNA damage where it may play a role in the transcriptional control of DNA repair mechanisms such as base and nucleotide excision repair and double strand break repair [145]. The transcription factor role of PARKIN therefore may act as a cellular defense mechanism against genotoxicity and suggests that DNA damage plays a pathogenic role in neurodegenerative disease such as PD [144, 145]. Recently, Shires etal. [146] have Page 9 of 20 Quinnetal. acta neuropathol commun (2020) 8:189 identified a role for nuclear PARKIN during hypoxia in activation of estrogen-related receptor α (ERRα), which is a transcription factor associated with mitochondrial metabolism and biogenesis. Interestingly, they also found that PARKIN mutants, ParkinR42P and ParkinG430D, are excluded from the nucleus and therefore unable to induce the transcription factor role of PARKIN. Therefore, the transcriptional roles as well as the mitophagic roles of PARKIN should be considered in PD as well as other neurodegenerative conditions.A Pink1 KO mouse model in which the pathogenic patient mutation G309D was inserted into exon 5 presented mitochondrial dysfunction leading to defects in ATP generation along with a reduction in dopamine in the nigrostriatal projection with a concurrent reduction in locomotor activity, but again without neurodegeneration [132]. Generation of a further Pink1 KO mouse, where exons 4–7 were deleted and consequently the majority of the kinase domain was removed, creating a nonsense mutation, caused impairment of dopamine release with striatal plasticity reduction. These impairments were rescued either in the presence of dopamine receptor agonists or due to stimulation of dopamine release, again highlighting the relevance of the nigrostriatal circuit [134]. In the same Pink1 KO mouse model, it was shown that relocation of PARKIN to mitochondria induced by a collapse of Δψm relies on PINK1 expression [147]. In another Pink1 KO mouse model, where exon 2 to exon 5 were replaced with a LacZ/Neo cassette, impaired dopamine release was also found. As compared to wild-type, dopamine from striatal slices of Pink1 KO mice decreased in an age-dependent manner. Additionally, it was found an age-dependent decrease in basal oxygen consumption rates and ATP levels in Pink1 KO mice, which suggests that decreased ATP generation may be the cause of the decreased dopamine release [148]. Recently, silencing of Pink1 in cultured mouse hippocampal neurons caused a decrease in postsynaptic density proteins PSD95 and Shank as well as glutamate receptor subunit NR2B and mGluR5. Interestingly, the authors found changes in actin regulatory proteins RhoGAP29 and ROCK2 which were concurrent with changes in spine morphology. The changes in dendritic spines, showing increased thin density spines and reduced head size of stubby spines, may be a sign of presymptomatic changes that lead to neurodegeneration in PD [149]. In comparison, a Pink1 KO rat model showed nigral neurodegeneration with 50% dopaminergic cell loss, an increase in striatal dopamine and serotonin content and significant motor deficits [136]. The inability of rodent models to recapitulate the severe neurodegeneration seen in PD patients may be due to low levels of PINK1, as has been identified in mice [150]. These studies also suggest there may be PINK1 independent mitophagy pathways yet to be eluded too. Recently, CRISPR/Cas9-mediated Pink1 deletion in rhesus macaques triggered severe neurodegeneration of the cortex, striatum and substantia nigra, with several newborns dying shortly after birth [151, 152]. These data suggest that in humans full PINK1 loss may lead to lethality in early development. Interestingly, a KO mouse model of the PINK1 OMM stabilisation protein PGAM5 leads to a more severe PD-like animal model than in Pink1 KO mouse models. The Pgam5 KO mice show a significant degeneration in dopaminergic neurons in addition to a PD-like movement disorder characterised by gait changes and bradykinesia [80]. Lastly, in light of mitochondria’s role in the immune system, we should look to reassess the many disorders associated with defective mitochondrial genes in terms of potential autoimmunity. PD, as one example, has been recently hotly debated as also being an autoimmune disease [153–158]. PINK1 and PARKIN have been found to regulate adaptive immunity, being key for mitochondrial antigen presentation in a mitophagy independent process. This process instead relies on the generation of MDVs with a direct correlation between the extent of MDV formation and the amount of mitochondrial antigen presentation. PINK1 and PARKIN inhibit this process, the presence of PARKIN was found to be key in preventing Snx9 being recruited to mitochondria and initiating MDV formation [159]. Further supporting this notion, it was recently found that intestinal infection of Pink1 KO mice with Gram-negative bacteria elicited mitochondrial antigen presentation and autoimmune mechanisms. These responses triggered mitochondrial-specific CD8+ T-cells that were found to induce dopaminergic neuron death. The infected Pink1 KO mice presented acute motor symptoms [153]. Therapeutics that influence mitochondrial immune regulation will be an exciting area to be developed in treating these diseases. Amyotrophic lateral sclerosis is a progressive and debilitating neuromuscular disease marked by degeneration of motor neurons in the brain and spinal cord, leading to muscle atrophy, paralysis and to death 3–5years after disease onset. 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