About

Matthew Farrer, PhD, is a professor of neurology at the University of Florida College of Medicine, with appointments in the Department of Neurology and the Evelyn F. and William L. McKnight Brain Institute. His work is critically acclaimed for its focus on the genetics and neuroscience of Parkinson's disease. His research aims to predict and prevent Parkinson's disease through molecular targets, tools, and models, emphasizing disease-modifying therapeutics and precision medicine. Dr. Farrer has made significant contributions to identifying genetic factors involved in neurodegenerative disorders, including the discovery of pathogenic variability in genes such as Leucine-Rich Repeat Kinase 2, Dynactin, and RAB32, among others. His team has also developed mouse models for Parkinson's disease and investigated the molecular mechanisms underlying alpha-synucleinopathies, including Lewy body dementia and multiple system atrophy. With a background in biochemistry and molecular and statistical genetics from St. Mary's Hospital Medical School in the UK, and further training in medical genetics and neurogenetics, Dr. Farrer has held prominent positions including Assistant Professor of Molecular Neuroscience, tenured Professor, Mayo Consultant, and Distinguished Mayo Investigator. He was awarded the Canada Excellence Research Chair in Neurogenetics and Neuroscience at the University of British Columbia, where his team achieved notable accomplishments such as identifying new genes and implementing high-throughput sequencing in clinical settings. His research endeavors are driven by a philosophy that understanding the molecular neuroscience of neurodegenerative diseases is essential for effective intervention and potential cures.

Research topics

• Neuroscience
• Biology
• Psychology
• Pathology
• Bioinformatics
• Medicine
• Genetics
• Immunology

Selected publications

• A case report of multiple system atrophy-mimics: Importance of comprehensive evaluation in suspected familial cases

  Medicine · 2026-01-23

  articleOpen access

  RATIONALE: Multiple system atrophy (MSA) is primarily a sporadic neurodegenerative disorder, and a positive family history is considered against the diagnosis. While rare familial clusters are reported, they pose a significant diagnostic challenge. This report describes 2 cousins with phenotypically classic MSA who underwent genetic testing to investigate a potential shared etiology, leading to a diagnosis of a rare MSA mimic. PATIENT CONCERNS: Case 1: a 77-year-old male presented with Parkinsonism (bradykinesia, resting tremor) and neurogenic orthostatic hypotension. Case 2: a 55-year-old female, case 1's 1st cousin, presented with progressive limb ataxia, dysarthria, and neurogenic orthostatic hypotension. Both patients reported a poor therapeutic response to levodopa and a progressive decline in functional mobility. DIAGNOSES: Initially, case 1 was diagnosed with clinically probable MSA with predominant Parkinsonism, and case 2 was diagnosed with clinically probable MSA with predominant cerebellar ataxia (MSA-C). However, post-genetic analysis, case 1 was definitively diagnosed with late-onset metachromatic leukodystrophy (MLD). Case 2 remained clinically classified as MSA-C as no significant genetic variants were identified. INTERVENTIONS: Clinical evaluation and levodopa trials were conducted for both patients. To investigate the suspected familial MSA cluster, whole-genome sequencing was performed for both individuals to identify shared pathogenic variants. OUTCOMES: Whole-genome sequencing identified biallelic pathogenic mutations in the arylsulfatase A gene in case 1, confirming MLD. No shared genetic etiology was found in case 2. The discovery of MLD in case 1 provided an alternative metabolic explanation for his symptoms, thereby refuting the initial hypothesis of a shared familial MSA link between the 2 cousins. LESSONS: This case highlights that late-onset MLD can closely mimic the clinical phenotype of MSA. Clinicians should maintain a high index of suspicion when encountering familial MSA. A comprehensive genetic evaluation is essential in such cases to exclude metabolic or hereditary mimics before concluding a rare familial presentation of a typically sporadic synucleinopathy.

  PublisherDOI

• Genetic testing for <i>SCA27B</i> in Korean multiple system atrophy

  Brain · 2025-07-17

  articleOpen accessSenior author
  PublisherDOI

• Peripheral inflammation mediates midbrain Lrrk2 kinase activity via Rab32 expression

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-06 · 1 citations

  preprintOpen accessSenior author

  ABSTRACT Mutations that increase leucine-rich repeat kinase 2 (LRRK2) activity confer significant risk for Parkinson’s disease (PD), yet incomplete disease penetrance suggest additional factors are required to manifest disease. We recently identified RAB32 Ser71Arg as a Mendelian gene for PD. Here, we establish Rab32 as a key mediator linking peripheral inflammation to Lrrk2 activation. We show that Rab32 and Rab38 expression are modestly, but inversely, correlated with their homolog Rab29. In vivo , peripheral lipopolysaccharide (LPS)-induced inflammation selectively induced Rab32 expression in midbrain Iba1 + microglia but not dopaminergic neurons, where it localized to Lamp1 + lysosomal compartments and correlated with Lrrk2 kinase activity. LPS similarly induces Rab32 expression in human induced pluripotent stem cell-derived microglia, demonstrating a unified biological response to inflammation across species. Promoter analysis identified Tfe3, a master regulator of lysosomal biogenesis and autophagy, as a key driver of Rab32 expression induced Lrrk2 kinase activation. During inflammation, Tfe3 translocated to the nucleus of midbrain Iba1 + microglia to induce Rab32 expression and Lrrk2 kinase activity. Knockdown of Tfe3, but not Tfeb, mitigates these effects, establishing Rab32 as a physiological rheostat of Lrrk2 activity. This mechanistic pathway enables peripheral inflammation to modulate LRRK2 activity and highlights Rab32/Tfe3 as a therapeutic targeting for neuroprotection in PD.

  PublisherOA PDFDOI

• The Genetic Epidemiology of Parkinson's Disease view

  The Lancet Neurology · 2025-03-19 · 1 citations

  letter1st authorCorresponding
  PublisherDOI

• Central biogenic amine deficiency with concomitant exploratory behavioral deficits in Dnajc12 knock-out mice

  npj Parkinson s Disease · 2025-05-30 · 2 citations

  articleOpen accessSenior author

  Bi-allelic autosomal recessive pathogenic variants in DNAJC12 lead to a constellation of neurological features, including young-onset Parkinson's disease. DNAJC12 is a co-chaperone for enzymes involved in biogenic amines synthesis. In vitro, we discovered overexpressed DNAJC12 forms a complex with guanine triphosphate cyclohydrolase 1 (GCH1), a rate-limiting enzyme in the synthesis of tetrahydrobiopterin, a cofactor for biogenic amine synthesis. We also confirm DNAJC12's interaction with tyrosine (TH) and tryptophan hydroxylases, paramount for dopamine (DA) and serotonin (5-HT) synthesis. In-vitro knock-down of DNAJC12 with a siRNA destabilizes DNAJC12-TH-GCH1 complex, whereas reciprocal co-overexpression of TH and GCH1 increases endogenous DNAJC12. Dnajc12 knock-out mice (DKO) exhibit reduced exploratory behavior at 3 months of age in open-field testing. In striatal tissue, total DA and 5-HT, and electrically evoked DA release are all reduced, with enhanced phosphorylation of Th at Ser31 and Ser40. DKO mice present models to develop/refine therapeutics approaches for biogenic amines disorders.

  PublisherOA PDFDOI

• Clinical Features of Families with a Novel Pathogenic Mutation in Sepiapterin Reductase

  International Journal of Molecular Sciences · 2025-03-27

  articleOpen access

  Sepiapterin Reductase Deficiency (SRD) is a rare inherited neurometabolic disorder caused by variants in the SPR gene, which may lead to developmental delays, psychomotor retardation, and cognitive impairments. Two consanguineous North African and Middle Eastern families are reported with multiple affected individuals presenting with developmental delay, ataxia, hypotonia, fatigue, and ptosis, or parkinsonism and cognitive impairment. Exome sequencing revealed a novel homozygous SPR c.560A&gt;G (p.Glu187Gly) mutation that segregates with disease. According to molecular dynamics analysis, the substitution is predicted to compromise structural integrity, likely affecting ligand binding and catalytic activity. Elevated cerebrospinal fluid sepiapterin and biopterin levels, along with low neurotransmitter levels, were concordant with a genetic diagnosis of SRD and the reclassification of this variant as pathogenic. SRD patients manifest a broad constellation of symptoms, albeit well-managed using low-dose L-dopa/carbidopa. This study highlights the value of genetic testing in expediting early diagnosis and intervention to mitigate the onset of this disorder.

  PublisherOA PDFDOI

• The age at onset of LRRK2 p.Gly2019Ser Parkinson’s disease across ancestries and countries of origin

  medRxiv · 2025-06-09

  preprintOpen access

  Abstract Objectives The LRRK2 p.Gly2019Ser pathogenic variant has reduced penetrance and presents a wide range of age at onset (AAO) in patients with Parkinson’s disease (PD). We aim to elucidate differences in the cumulative incidence of LRRK2 p.Gly2019Ser - related PD ( LRRK2 -PD) between ancestries and countries. Methods We included N=922 unrelated LRRK2 p.Gly2019Ser variant carriers (affected: N=762, unaffected: N=160) from the Global Parkinson’s Genetics Program (GP2) in addition to cohorts recruited from the Israeli Ashkenazi Jewish and Tunisian Arab-Berber population. The p.Gly2019Ser variant was present in five ancestries: Ashkenazi Jewish (N=534), North African (N=223), European (N=132), Middle Eastern (N=19) and Latino and Indigenous people of the Americas (N=14). In addition to ancestry derived from the genetic data, we assessed the country of origin in our analysis. The Cox proportional-hazards model and Kaplan-Meier analysis were applied to examine differences in cumulative incidence. All analyses were adjusted for biological sex, and the outcome variable was AAO, including affected and unaffected variant carriers with right censoring for affection status, and all analysis were exploratory. Results The median AAO of LRRK2 -PD was five years younger in the North African (HR=1.48, 95% CI: 1.18-1.86, p=7.0×10 −4 ) compared to the European ancestry group. In contrast, the median AAO was five years older in the Ashkenazi Jewish (HR=0.61, 95% CI: 0.50-0.75, p=4.0×10 −6 ) compared to the European ancestry group. Additionally, patients from Israel (HR=1.59, 95% CI: 1.30-1.39, p=4.0×10 −6 ) and Tunisia (HR=2.57, 95% CI: 2.16-3.06, p&lt;2.0×10 −16 ) had a median 5-year and 10-year younger AAO compared to patients from the USA, respectively. Lastly, when focusing only on individuals with an Ashkenazi Jewish background, patients from Israel still had a younger AAO than those from the USA (HR=1.82, 95% CI: 1.48-2.24, p=1.5×10 −8 ). Analogously, assessing only patients from the USA, the Ashkenazi Jewish ancestry group still had an older AAO than the European ancestry group (HR=0.51, 95% CI: 0.39-0.67, p=1.3×10 −6 ). Discussion Our results provide evidence that a person’s genetic ancestry and country of origin are associated with the AAO of LRRK2 -PD. This highlights the potential impact of both genetic and environmental factors on LRRK2 -PD AAO.

  PublisherOA PDFDOI

• Complementarity of long-read sequencing and optical genome mapping in Parkinson’s disease

  medRxiv · 2025-08-21

  preprintOpen access

  Abstract Background With third-generation long-read sequencing (LRS) platforms and optical genome mapping technologies (OGM), the ability to detect large and complex structural variants (SVs) is rapidly advancing. This has led to the discovery of novel pathogenic variants, such as large deletions and insertions, in neurodegenerative movement disorders. Thus, we aimed to systematically examine the applicability of the combined application of LRS and OGM in Parkinson’s disease (PD). Methods Ultra-high molecular weight DNA was derived from blood and fibroblast cultures and used for Oxford Nanopore Technologies (ONT) LRS and OGM. We included 19 patients with mostly early-onset PD. Variant calling was performed with the tools Sniffles2 and Spectre for ONT and the Bionano Solve software for OGM. The size distribution of deletions and insertions was compared, and a subsequent analysis pipeline based on AnnotSV, SVAFotate, and needLR was employed to annotate and filter for rare (population allele frequency ≤1%) or potentially pathogenic (CADD-SV &gt;20) variants affecting 134 known movement disorder genes. Results Both methods identified SVs ≥50 kb; however, OGM detected fewer SVs (49,677) with a larger mean size of 25 kb (SD=209 kb) compared to ONT (92,030, mean=17 kb, SD=1.1 Mb). In the size bracket of 50-80 kb, which falls outside the ideal detection range of Sniffles2 and Spectre, OGM detected 384 deletions and insertions, compared to six detected by ONT. OGM detected significantly larger deletions and insertions than ONT (p-value &lt;2.2×10 -16 ). Regarding known movement disorder genes, a heterozygous intergenic deletion (195 kb) near ITPR1 was detected by both methods, and OGM validated a previously published 7 Mb inversion in PRKN . Heterozygous deletions in ATXN2 (1.4 kb), SUCLA2 (1.7 kb), and PNKD (2.6 kb) were detected by OGM and confirmed to be intronic by ONT. Conclusion OGM allows for better detection of large insertions and can serve as a powerful first-line method to detect large pathogenic variants. However, it greatly benefits from a high-resolution sequencing technique like ONT to refine breakpoint positions. Despite certain limitations, ONT proved to be highly capable of detecting large variants independently; thus, it allows for a highly complementary assessment and validation of structural variation in combination with OGM.

  PublisherOA PDFDOI

• Intronic <i>FGF14</i> GAA repeat expansions impact progression and survival in multiple system atrophy

  Brain · 2025-04-16 · 5 citations

  articleOpen access

  Partial phenotypic overlap has been suggested between multiple system atrophy and spinocerebellar ataxia 27B, the autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. In this study, we investigated the frequency of FGF14 GAA•TTC repeat expansion in clinically diagnosed and pathologically confirmed multiple system atrophy cases. We screened 657 multiple system atrophy cases (193 clinically diagnosed and 464 pathologically confirmed) and 1003 controls. The FGF14 repeat locus was genotyped using long-range PCR and bidirectional repeat-primed PCRs, and expansions were confirmed with targeted long-read Oxford Nanopore Technologies sequencing. We identified 19 multiple system atrophy cases carrying an FGF14 GAA≥250 expansion (2.89%, n = 19/657), a significantly higher frequency than in controls (1.40%, n = 12/1003) (P = 0.04). Long-read Oxford Nanopore Technologies sequencing confirmed repeat sizes and polymorphisms detected by PCR, with high concordance (Pearson's r = 0.99, P < 0.0001). Seven multiple system atrophy patients had a pathogenic FGF14 GAA≥300 expansion (five pathologically confirmed and two clinically diagnosed), and 12 had intermediate GAA250-299 expansion (six pathologically confirmed and six clinically diagnosed). A similar proportion of cerebellar-predominant and parkinsonism-predominant multiple system atrophy cases had FGF14 expansions. Multiple system atrophy patients carrying an FGF14 GAA≥250 expansion exhibited severe gait ataxia, autonomic dysfunction and parkinsonism, in keeping with a multiple system atrophy phenotype, with a faster progression to falls (P = 0.03) and regular wheelchair use (P = 0.02) in comparison to the multiple system atrophy cases without FGF14 GAA expansion. The length of the GAA•TTC repeat expansion lengths was inversely correlated with survival in multiple system atrophy patients (r = -0.67; P = 0.02) but not with age of onset. Therefore, screening for FGF14 GAA•TTC repeat expansion should be considered for multiple system atrophy patients with rapid loss of mobility and for complete diagnostic accuracy at inclusion in disease-modifying multiple system atrophy drug trials.

  PublisherOA PDFDOI

• TDP-43 loss of function drives aberrant splicing in Parkinson’s disease

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-09

  preprintOpen access

  Introductory paragraph While mRNA splicing dysregulation is a well-established contributor to neurodegeneration in disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), its role in Parkinson’s disease (PD) remains underexplored. Here, we analyse transcriptomic data from &gt;500 post-mortem human brain samples from individuals with and without PD to show that splicing alterations are frequently detected. Differentially spliced genes were significantly more enriched for those causally-implicated in both PD and ALS than genes that were differentially expressed. Furthermore, we observed a strong association between these splicing alterations and dysfunction of the RNA-binding protein (RBP), TAR DNA-binding protein 43 (TDP-43). Strikingly, genes and exon junctions affected by TDP-43 knockdown overlapped significantly with those dysregulated across brain regions in PD. In brains from individuals with the LRRK2 c.6055G&gt;A (p.G2019S) mutation, the most common genetic cause of PD, we also observed significant enrichment of TDP-43-dependent splicing changes. This finding was corroborated in human pluripotent stem cell-derived midbrain dopaminergic neurons and a LRRK2 p.G2019S knock-in mouse model, where reduced nuclear TDP-43 levels evidenced the well-recognised loss-of-function mechanism contributing to splicing dysregulation. By leveraging our RNA-based analyses we predicted TDP-43-dependent novel peptide sequences and validated their existence within human LRRK2 mutation mDNs, while also demonstrating an overall loss of protein and mRNA expression in mis-spliced genes. Collectively, our findings reveal that PD is marked by extensive splicing dysregulation dependent on TDP-43, making TDP-43 a promising new therapeutic target in PD.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01ES013941

  NIH · $1.1M · 2008

• NIH Grant R21NS064885

  NIH · $153k · 2010

• NIH Grant R01AG022579

  NIH · $1.2M · 2007

• NIH Grant P01NS040256

  NIH · $12.2M · 2004

• NIH Grant P01AG017216

  NIH · $14.7M · 2012

Frequent coauthors

• Zbigniew K. Wszołek

  WinnMed

  478 shared

• Owen A. Ross

  Jacksonville College

  456 shared

• Ryan J. Uitti

  Mayo Clinic in Florida

  357 shared

• Andrew Singleton

  National Institute on Aging

  330 shared

• Dennis W. Dickson

  Mayo Clinic in Florida

  326 shared

• John Hardy

  University College London

  300 shared

• Alexis Brice

  Sorbonne Université

  286 shared

• Jan Aasly

  St Olav's University Hospital

  283 shared

Labs

• iBRAIN LabPI

Education

• M.D.

  University of Florida

• B.S.

  University of Florida

Awards & honors

• Canada Excellence Research Laureate 2017 (Government of Cana…
• 9th Donald Calne Lectureship 2012 (Parkinson Society Canada)
• Pritzker Prize Nomination 2011 (Parkinson Society Canada)
• Michael J. Fox Foundation Health Care Hero 2009
• Jacksonville Business Journal Distinguished Investigator Awa…