Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.

OBJECTIVE: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. METHODS: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. RESULTS: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. INTERPRETATION: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.

A human minisatellite hosts an alternative transcription start site for NPRL3 driving its expression in a repeat number-dependent manner.

Minisatellites, also called variable number of tandem repeats (VNTRs), are a class of repetitive elements that may affect gene expression at multiple levels and have been correlated to disease. Their identification and role as expression quantitative trait loci (eQTL) have been limited by their absence in comparative genomic hybridization and single nucleotide polymorphisms arrays. By taking advantage of cap analysis of gene expression (CAGE), we describe a new example of a minisatellite hosting a transcription start site (TSS) which expression is dependent on the repeat number. It is located in the third intron of the gene nitrogen permease regulator like protein 3 (NPRL3). NPRL3 is a component of the GAP activity toward rags 1 protein complex that inhibits mammalian target of rapamycin complex 1 (mTORC1) activity and it is found mutated in familial focal cortical dysplasia and familial focal epilepsy. CAGE tags represent an alternative TSS identifying TAGNPRL3 messenger RNAs (mRNAs). TAGNPRL3 is expressed in red blood cells both at mRNA and protein levels, it interacts with its protein partner NPRL2 and its overexpression inhibits cell proliferation. This study provides an example of a minisatellite that is both a TSS and an eQTL as well as identifies a new VNTR that may modify mTORC1 activity.

Penetrance of Glucocerebrosidase (GBA) Mutations in Parkinson's Disease: A Kin Cohort Study.

BACKGROUND: Homozygous glucocerebrosidase mutations cause Gaucher disease, whereas heterozygous mutations are the most important genetic risk factor for Parkinson's disease (PD). The penetrance of heterozygous glucocerebrosidase mutations for PD is variable (10%-30%), depends on the population studied, and has only been assessed in Gaucher disease or familial PD. The aim of this study was to assess the penetrance of glucocerebrosidase mutations in PD in unselected PD patients. METHODS: The penetrance of glucocerebrosidase mutations was estimated using the kin-cohort method. RESULTS: Data on family history were available for 63 of 123 PD glucocerebrosidase mutation carriers, identified among 2843 unrelated consecutive PD patients. Three hundred eighty-one first-degree relatives were analyzed. The risk of developing PD was 10% at 60 years, 16% at 70 years, and 19% at 80 years. CONCLUSIONS: The estimated penetrance of glucocerebrosidase mutations in unselected PD patients is higher than that estimated in Gaucher disease cohorts and lower than that estimated in familial PD cohorts. © 2020 International Parkinson and Movement Disorder Society.

Nonsteroidal Anti-inflammatory Use and LRRK2 Parkinson's Disease Penetrance.

BACKGROUND: The penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown. OBJECTIVES: The objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD. METHODS: Symptomatic ("LRRK2-PD") and asymptomatic ("LRRK2-non-PD") participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups. RESULTS: A total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21-0.57) and in both pathogenic and risk variant carriers (ORPathogenic , 0.38; 95% CI, 0.21-0.67 and ORRiskVariant , 0.19; 95% CI, 0.04-0.99). Similar associations were observed for ibuprofen and aspirin separately (ORIbuprofen , 0.19; 95% CI, 0.07-0.50 and ORAspirin , 0.51; 95% CI, 0.28-0.91). CONCLUSIONS: Regular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association. © 2020 International Parkinson and Movement Disorder Society.

DNAJC12 and dopa-responsive nonprogressive parkinsonism.

Biallelic DNAJC12 mutations were described in children with hyperphenylalaninemia, neurodevelopmental delay, and dystonia. We identified DNAJC12 homozygous null variants (c.187A>T;p.K63* and c.79-2A>G;p.V27Wfs*14) in two kindreds with early-onset parkinsonism. Both probands had mild intellectual disability, mild nonprogressive, motor symptoms, sustained benefit from small dose of levodopa, and substantial worsening of symptoms after levodopa discontinuation. Neuropathology (Proband-A) revealed no alpha-synuclein pathology, and substantia nigra depigmentation with moderate cell loss. DNAJC12 transcripts were reduced in both patients. Our results suggest that DNAJC12 mutations (absent in 500 early-onset patients with Parkinson's disease) rarely cause dopa-responsive nonprogressive parkinsonism in adulthood, but broaden the clinical spectrum of DNAJC12 deficiency. Ann Neurol 2017;82:640-646.

Survival and dementia in GBA-associated Parkinson's disease: The mutation matters.

OBJECTIVE: The objective of this work was to investigate survival, dementia, and genotype-phenotype correlations in patients with Parkinson's disease (PD) with and without mutations on the glucocerebrosidase gene (GBA). METHODS: We included 2,764 unrelated consecutive PD patients: 123 GBA carriers (67 mild-p.N370S and 56 severe mainly p.L444P) and 2,641 noncarriers. Brain perfusion and dopamine transporter imaging was analyzed, including dementia with Lewy Bodies (DLB) as an additional control group. RESULTS: Multivariable analysis adjusted by sex, age at onset, and disease duration attributed to GBA carriers a greater risk for dementia (hazard ratio [HR] = 3.16; p < 0.001) and death (HR = 1.85; p = 0.002) than noncarriers. When dementia was introduced in the model as a time-dependent covariate, the mortality risk remained greater in carriers (HR = 1.65; p = 0.016), suggesting that other clinical features are likely to contribute to reduced survival. At last examination, GBA carriers had worse motor symptoms, particularly nondopaminergic features. Carriers of severe mutations had greater risk for dementia compared to mild mutations (p < 0.001), but similar mortality risk. Consistent with clinical data, GBA carriers showed reduced posterior parietal and occipital cortical synaptic activity and nigrostriatal function than PD noncarriers. Neuroimaging features of carriers of mild mutations overlapped with PD noncarriers, whereas carriers of severe mutations were closer to DLB. INTERPRETATION: Survival is reduced in GBA carriers compared to noncarriers; this seems to be partially independent from the increased risk for early dementia. The risk for dementia is strongly modulated by type of mutation. In the clinical continuum between PD and DLB, patients with GBA mutations seem to localize midway, with carriers of severe mutations closer to DLB than to idiopathic PD. Ann Neurol 2016;80:662-673.

Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non-Ashkenazi Jewish ancestry.

BACKGROUND: Penetrance estimates of the leucine-rich repeat kinase 2 (LRRK2) p.G2019S mutation for PD vary widely (24%-100%). The p.G2019S penetrance in individuals of Ashkenazi Jewish ancestry has been estimated as 25%, adjusted for multiple covariates. It is unknown whether penetrance varies among different ethnic groups. The objective of this study was to estimate the penetrance of p.G2019S in individuals of non-Ashkenazi Jewish ancestry and compare penetrance between Ashkenazi Jews and non-Ashkenazi Jews to age 80. METHODS: The kin-cohort method was used to estimate penetrance in 474 first-degree relatives of 69 non-Ashkenazi Jewish LRRK2 p.G2019S carrier probands at 8 sites from the Michael J. Fox LRRK2 Cohort Consortium. An identical validated family history interview was administered to assess age at onset of PD, current age, or age at death for relatives in different ethnic groups at each site. Neurological examination and LRRK2 genotype of relatives were included when available. RESULTS: Risk of PD in non-Ashkenazi Jewish relatives who carry a LRRK2 p.G2019S mutation was 42.5% (95% confidence interval [CI]: 26.3%-65.8%) to age 80, which is not significantly higher than the previously estimated 25% (95% CI: 16.7%-34.2%) in Ashkenazi Jewish carrier relatives. The penetrance of PD to age 80 in LRRK2 p.G2019S mutation carrier relatives was significantly higher than the noncarrier relatives, as seen in Ashkenazi Jewish relatives. CONCLUSIONS: The similar penetrance of LRRK2 p.G2019S estimated in Ashkenazi Jewish carriers and non-Ashkenazi Jewish carriers confirms that p.G2019S penetrance is 25% to 42.5% at age 80 in all populations analyzed. © 2017 International Parkinson and Movement Disorder Society.

An exome study of Parkinson's disease in Sardinia, a Mediterranean genetic isolate.

Parkinson's disease (PD) is a common neurodegenerative disorder of complex aetiology. Rare, highly penetrant PD-causing mutations and common risk factors of small effect size have been identified in several genes/loci. However, these mutations and risk factors only explain a fraction of the disease burden, suggesting that additional, substantial genetic determinants remain to be found. Genetically isolated populations offer advantages for dissecting the genetic architecture of complex disorders, such as PD. We performed exome sequencing in 100 unrelated PD patients from Sardinia, a genetic isolate. SNPs absent from dbSNP129 and 1000 Genomes, shared by at least five patients, and of functional effects were genotyped in an independent Sardinian case-control sample (n = 500). Variants associated with PD with nominal p value <0.05 and those with odds ratio (OR) ≥3 were validated by Sanger sequencing and typed in a replication sample of 2965 patients and 2678 controls from Italy, Spain, and Portugal. We identified novel moderately rare variants in several genes, including SCAPER, HYDIN, UBE2H, EZR, MMRN2 and OGFOD1 that were specifically present in PD patients or enriched among them, nominating these as novel candidate risk genes for PD, although no variants achieved genome-wide significance after Bonferroni correction. Our results suggest that the genetic bases of PD are highly heterogeneous, with implications for the design of future large-scale exome or whole-genome analyses of this disease.

Parkinson's disease beyond 20†years.

BACKGROUND: A very limited number of studies report data on the clinical features of Parkinson's disease (PD) 20 years after onset and beyond. OBJECTIVE: To characterise PD 20 years after onset, investigating the impact of age at onset and disease duration on the clinical picture and the predictors of outcomes in patients reaching the 20-year time point. METHODS: We conducted a retrospective, cross-sectional study and a longitudinal study. All case visits of patients with a disease duration ≥20 years (N=401) were stratified by disease duration (20-22, 23-25, ≥26 years) and by age at onset (cut-off, 50 years). Patients with a disease duration of 20-22 years (N=320) were prospectively followed up for a median of 45 months (IQR 23-89) for the new occurrence of fracture, percutaneous endoscopic gastrostomy, institutionalisation, confinement to a wheelchair or bed and death. RESULTS: Older age at onset and longer disease duration were independently associated with a higher prevalence of major motor and non-motor milestones of disease disability (no interaction observed). In the longitudinal study, the most frequent outcomes were death (N=92), confinement to a wheelchair or bed (N=67) and fracture (N=52). Mortality was associated with the gender: male, older age, dysphagia, orthostatic hypotension, postural instability, fractures and institutionalisation. Fracture was associated with postural instability. Predictors of permanent confinement to a wheelchair or bed were older age, postural instability and institutionalisation. Comorbid dementia at the 20-year examination did not predict any of the outcomes. CONCLUSIONS: Age at onset and disease duration are independent determinants of the clinical features of PD beyond 20 years. Non-motor symptoms depend more on age at onset rather than the disease duration itself. Non-levodopa-responsive axial symptoms are the main predictors of all relevant outcomes.

Alpha-synuclein repeat variants and survival in Parkinson's disease.

OBJECTIVES: To determine whether α-synuclein dinucleotide repeat (REP1) genotypes are associated with survival in Parkinson's disease (PD). METHODS: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium provided REP1 genotypes and baseline and follow-up clinical data for cases. The primary outcome was time to death. Cox proportional hazards regression models were used to assess the association of REP1 genotypes with survival. RESULTS: Twenty-one sites contributed data for 6,154 cases. There was no significant association between α-synuclein REP1 genotypes and survival in PD. However, there was a significant association between REP1 genotypes and age at onset of PD (hazard ratio: 1.06; 95% confidence interval: 1.01-1.10; P value = 0.01). CONCLUSIONS: In our large consortium study, α-synuclein REP1 genotypes were not associated with survival in PD. Further studies of α-synuclein's role in disease progression and long-term outcomes are needed.

Cyclin-G-associated kinase modifies α-synuclein expression levels and toxicity in Parkinson's disease: results from the GenePD Study.

Although family history is a well-established risk factor for Parkinson's disease (PD), fewer than 5% of PD cases can be attributed to known genetic mutations. The etiology for the remainder of PD cases is unclear; however, neuronal accumulation of the protein α-synuclein is common to nearly all patients, implicating pathways that influence α-synuclein in PD pathogenesis. We report a genome-wide significant association (P = 3.97 × 10(-8)) between a polymorphism, rs1564282, in the cyclin-G-associated kinase (GAK) gene and increased PD risk, with a meta-analysis odds ratio of 1.48. This association result is based on the meta-analysis of three publicly available PD case-control genome-wide association study and genotyping from a new, independent Italian cohort. Microarray expression analysis of post-mortem frontal cortex from PD and control brains demonstrates a significant association between rs1564282 and higher α-synuclein expression, a known cause of early onset PD. Functional knockdown of GAK in cell culture causes a significant increase in toxicity when α-synuclein is over-expressed. Furthermore, knockdown of GAK in rat primary neurons expressing the A53T mutation of α-synuclein, a well-established model for PD, decreases cell viability. These observations provide evidence that GAK is associated with PD risk and suggest that GAK and α-synuclein interact in a pathway involved in PD pathogenesis. The GAK protein, a serine/threonine kinase, belongs to a family of proteins commonly targeted for drug development. This, combined with GAK's observed relationship to the levels of α-synuclein expression and toxicity, suggests that the protein is an attractive therapeutic target for the treatment of PD.

Generation and characterization of induced pluripotent stem cells from a Parkinson's disease patient carrying the digenic LRRK2 p.G2019S and GBA1 p.N409S mutations.

We describe an induced pluripotent stem cell (iPSC) line that was derived from fibroblasts obtained from a Parkinson's disease (PD) patient carrying the p.G2019S mutation in the LRRK2 gene and the p.N409S mutation in the GBA1 gene. iPSCs were generated via Sendai virus transduction of Yamanaka factors. The presence of GBA1 p.N409S and LRRK2 p.G2019S was confirmed by Sanger sequencing. The iPSCs express pluripotency markers, are capable of in vitro differentiation into the three germ layers and have a normal karyotype. The newly generated line will be used for in vitro PD modeling by investigating the role of each mutation in iPSC-derived dopaminergic neurons.

Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis.

OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD. METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios. RESULTS: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 × 10(-6) for ALS and p = 4.3 × 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD. INTERPRETATION: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD.

TARDBP mutations in a cohort of Italian patients with Parkinson's disease and atypical parkinsonisms.

Background: Aggregates of TAR DNA-binding protein of 43 kDa (TDP-43) represent the pathological hallmark of most amyotrophic lateral sclerosis (ALS) and of nearly 50% of frontotemporal dementia (FTD) cases but were also observed to occur as secondary neuropathology in the nervous tissue of patients with different neurodegenerative diseases, including Parkinson's disease (PD) and atypical parkinsonism. Mutations of TARDBP gene, mainly in exon 6 hotspot, have been reported to be causative of some forms of ALS and FTD, with clinical signs of parkinsonism observed in few mutation carriers. Methods: Direct DNA sequencing of TARDBP exon 6 was performed in a large Italian cohort of 735 patients affected by PD (354 familial and 381 sporadic) and 142 affected by atypical parkinsonism, including 39 corticobasal syndrome (CBS) and 103 progressive sopranuclear palsy (PSP). Sequencing data from 1710 healthy, ethnically matched controls were already available. Results: Four TARDBP missense variants (p.N267S, p. G294A, p.G295S, p.S393L) were identified in four patients with typical PD and in two individuals with atypical parkinsonism (1 CBS and 1 PSP). None of the detected mutations were found in healthy controls and only the variant p.N267S was previously described in association to idiopathic familial and sporadic PD and to CBS. Conclusion: In this study we provide further insight into the clinical phenotypic heterogeneity associated with TARDBP mutations, which expands beyond the classical ALS and FTD diseases to include also PD and atypical parkinsonism, although with a low mutational frequency, varying considerably in different Caucasian populations. In addition, our study extends the spectrum of TARDBP pathogenetic mutations found in familial and sporadic PD.

VPS13C-associated Parkinson's disease: Two novel cases and review of the literature.

VPS13C is a protein-coding gene involved in the regulation of mitochondrial function through the endolysosomal pathway in neurons. Homozygous and compound heterozygous VPS13C mutations are etiologically associated with early-onset Parkinson's disease (PD). Moreover, recent studies linked biallelic VPS13C mutations with the development of dementia with Lewy bodies (DLB). Neuropathological studies on two mutated subjects showed diffuse Lewy body disease. In this article, we report the clinical and genetic findings of two subjects affected by early-onset PD carrying three novel VPS13C mutations (i.e., one homozygous and one compound heterozygous), and review the previous literature on the genetic and clinical findings of VPS13C-mutated patients, contributing to the knowledge of this rare genetic alpha-synucleinopathy.

GIGYF2 gene disruption in mice results in neurodegeneration and altered insulin-like growth factor signaling.

Grb10-Interacting GYF Protein 2 (GIGYF2) was initially identified through its interaction with Grb10, an adapter protein that binds activated IGF-I and insulin receptors. The GIGYF2 gene maps to human chromosome 2q37 within a region linked to familial Parkinson's disease (PARK11 locus), and association of GIGYF2 mutations with Parkinson's disease has been described in some but not other recent publications. This study investigated the consequences of Gigyf2 gene disruption in mice. Gigyf2 null mice undergo apparently normal embryonic development, but fail to feed and die within the first 2 post-natal days. Heterozygous Gigyf2(+/-) mice survive to adulthood with no evident metabolic or growth defects. At 12-15 months of age, the Gigyf2(+/-) mice begin to exhibit motor dysfunction manifested as decreased balance time on a rotating horizontal rod. This is associated with histopathological evidence of neurodegeneration and rare intracytoplasmic Lewy body-like inclusions in spinal anterior horn motor neurons. There are alpha-synuclein positive neuritic plaques in the brainstem and cerebellum, but no abnormalities in the substantia nigra. Primary cultured embryo fibroblasts from Gigyf2 null mice exhibit decreased IGF-I-stimulated IGF-I receptor tyrosine phosphorylation and augmented ERK1/2 phosphorylation. These data provide further evidence for an important role of GIGYF2 in age-related neurodegeneration and IGF pathway signaling.

Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease.

The genetic basis for association of the PARK11 region of chromosome 2 with familial Parkinson disease (PD) is unknown. This study examined the GIGYF2 (Grb10-Interacting GYF Protein-2) (TNRC15) gene, which contains the PARK11 microsatellite marker with the highest linkage score (D2S206, LOD 5.14). The 27 coding exons of the GIGYF2 gene were sequenced in 123 Italian and 126 French patients with familial PD, plus 131 Italian and 96 French controls. A total of seven different GIGYF2 missense mutations resulting in single amino acid substitutions were present in 12 unrelated PD index patients (4.8%) and not in controls. Three amino acid insertions or deletions were found in four other index patients and absent in controls. Specific exon sequencing showed that these ten sequence changes were absent from a further 91 controls. In four families with amino acid substitutions in which at least one other PD case was available, the GIGYF2 mutations (Asn56Ser, Thr112Ala, and Asp606Glu) segregated with PD. There were, however, two unaffected carriers in one family, suggesting age-dependent or incomplete penetrance. One index case (PD onset age 33) inherited a GIGYF2 mutation (Ile278Val) from her affected father (PD onset age 66) and a previously described PD-linked mutation in the LRRK2 gene (Ile1371Val) from her affected mother (PD onset age 61). The earlier onset and severe clinical course in the index patient suggest additive effects of the GIGYF2 and LRRK2 mutations. These data strongly support GIGYF2 as a PARK11 gene with a causal role in familial PD.

TNF-α and α-synuclein fibrils differently regulate human astrocyte immune reactivity and impair mitochondrial respiration.

Here, we examine the cellular changes triggered by tumor necrosis factor alpha (TNF-α) and different alpha-synuclein (αSYN) species in astrocytes derived from induced pluripotent stem cells. Human astrocytes treated with TNF-α display a strong reactive pro-inflammatory phenotype with upregulation of pro-inflammatory gene networks, activation of the nuclear factor κB (NF-κB) pathway, and release of pro-inflammatory cytokines, whereas those treated with high-molecular-weight αSYN fibrils acquire a reactive antigen (cross)-presenting phenotype with upregulation of major histocompatibility complex (MHC) genes and increased human leukocyte antigen (HLA) molecules at the cell surface. Surprisingly, the cell surface location of MHC proteins is abrogated by larger F110 fibrillar polymorphs, despite the upregulation of MHC genes. Interestingly, TNF-α and αSYN fibrils compete to drive the astrocyte immune reactive response. The astrocyte immune responses are accompanied by an impaired mitochondrial respiration, which is exacerbated in Parkinson's disease (PD) astrocytes. Our data provide evidence for astrocytic involvement in PD pathogenesis and reveal their complex immune reactive responses to exogenous stressors.