Pathways to Parkinsonism Redux: convergent pathobiological mechanisms in genetics of Parkinson's disease
Open accessAbstract
In the past few years, there have been a large number of genes identified that contribute to the lifetime risk of Parkinson's disease (PD). Some genes follow a Mendelian inheritance pattern, but others are risk factors for apparently sporadic PD. Here, we will focus on those genes nominated by genome-wide association studies (GWAS) in sporadic PD, with a particular emphasis on genes that overlap between familial and sporadic disease such as those encoding a-synuclein (SNCA), tau (MAPT), and leucine-rich repeat kinase 2 (LRRK2). We will advance the view that there are likely relationships between these genes that map not only to neuronal processes, but also to neuroinflammation. We will particularly discuss evidence for a role of PD proteins in microglial activation and regulation of the autophagy-lysosome system that is dependent on microtubule transport in neurons. Thus, there are at least two non-mutually exclusive pathways that include both non-cell-autonomous and cell-autonomous mechanisms in the PD brain. Collectively, these data have highlighted the amount of progress made in understanding PD and suggest ways forward to further dissect this disorder.
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LRRK2 is one of the most commonly mutated genes in both idiopathic and familial Parkinson disease.
“genetic studies have identified the leucine-rich repeat kinase 2 (LRRK2) as one of the most commonly mutated genes in both idiopathic and familial PD (159).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [159]
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“TLR4 has specifically been shown to mediate cell death in a murine MPTP model of PD (70) whilst polymorphisms in the TLR4 gene were recently proposed to alter the risk of developing sporadic PD in Han Chinese population (71), although this result has not been replicated at the time of writing.”
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- Authors
- Kumaran, R., & Cookson, M. R.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Cookson, Mark R.
- ORCID
- Cookson, Mark R.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-06-22
- Volume
- 24
- Issue
- R1
- Pages
- R32-R44
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC4571999
- OpenAlex
- W1757839782
- Cited by
- 86
- References
- 136
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 6 · 2023: 5 · 2022: 4 · 2021: 8 · 2020: 9 · 2019: 4 · 2018: 8 · 2017: 23 · 2016: 10
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- Locations
- Human Molecular Genetics (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Funders
- Intramural Research Program
- NIH
- National Institute of Aging
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Parkinson's disease, sporadic Parkinson's disease, familial Parkinson's disease, genetic risk factors, alpha-synuclein, tau protein, MAPT, LRRK2, neuroinflammation, microglial activation, autophagy-lysosome system, microtubule transport, non-cell-autonomous mechanisms, cell-autonomous mechanisms
- MeSH terms
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Animals, Humans, Inflammation, Parkinson Disease, tau Proteins, Protein Serine-Threonine Kinases, Autonomic Pathways, Parkinsonian Disorders, alpha-Synuclein, Metabolic Networks and Pathways, Genome-Wide Association Study
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