Genes Associated with Parkinson's.

Parkinson's isn't one disease. It's many diseases converging on dopamine neurons. Understanding the pathways helps you protect them.

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Important context.

Only 10-15% of Parkinson's cases have a clear genetic cause. The rest are "sporadic"—caused by gene-environment interactions. Even among those with strong genetic risk factors, penetrance is incomplete. Having the gene doesn't mean you'll get PD.

The genes.

PD genes cluster into protein aggregation, mitochondrial function, autophagy, dopamine metabolism, and neuroinflammation.

Alpha-Synuclein & Protein Aggregation

Parkinson's is characterized by Lewy bodies—clumps of misfolded alpha-synuclein protein.

SNCA

Alpha-Synuclein

Synaptic vesicle function and neurotransmitter release

Variant: Duplications/triplications cause familial PD; common variants affect risk

The protein that misfolds and forms Lewy bodies—the hallmark of PD

GBA

Glucocerebrosidase

Lysosomal enzyme that breaks down glucocerebroside

Variant: Mutations are the most common genetic risk factor for PD

Gaucher disease gene—heterozygotes have 5-10x increased PD risk

Mitochondrial Function

Dopamine neurons have extremely high energy demands. Mitochondrial dysfunction is central to PD.

PINK1

PTEN-Induced Kinase 1

Marks damaged mitochondria for destruction (mitophagy)

Variant: Recessive mutations cause early-onset PD

Works with Parkin to clear damaged mitochondria

PRKN (Parkin)

Parkin RBR E3 Ubiquitin Protein Ligase

Tags damaged mitochondria for autophagy

Variant: Most common cause of early-onset PD

Exercise activates the Parkin pathway—protective

DJ-1 (PARK7)

Protein Deglycase DJ-1

Protects against oxidative stress in mitochondria

Variant: Rare recessive mutations cause early-onset PD

Sensor for oxidative stress—early warning system

Autophagy & Lysosomal Function

Clearing damaged proteins and organelles is critical for neuron survival.

LRRK2

Leucine-Rich Repeat Kinase 2

Regulates autophagy, vesicle trafficking, and immune function

Variant: G2019S is the most common cause of familial PD

Also involved in Crohn's disease—gut-brain connection

VPS35

Vacuolar Protein Sorting 35

Retromer complex component for protein recycling

Variant: D620N mutation causes autosomal dominant PD

Affects trafficking of key receptors

ATP13A2

ATPase Cation Transporting 13A2

Lysosomal membrane protein maintaining function

Variant: Mutations cause Kufor-Rakeb syndrome (early PD with dementia)

Links lysosomal dysfunction to neurodegeneration

Dopamine Metabolism

Dopamine itself can be toxic if not properly handled.

MAOB

Monoamine Oxidase B

Breaks down dopamine in the brain

Variant: Variants affect dopamine metabolism

Target of MAO-B inhibitors like selegiline and rasagiline

DDC

DOPA Decarboxylase

Converts L-DOPA to dopamine

Variant: Affects L-DOPA response

Why L-DOPA therapy works—bypasses tyrosine hydroxylase

Immune & Inflammatory

Neuroinflammation plays a key role in PD progression.

HLA-DRB1

Major Histocompatibility Complex, Class II

Immune system antigen presentation

Variant: Variants associated with PD risk

Suggests autoimmune component to PD

TREM2

Triggering Receptor Expressed on Myeloid Cells 2

Microglial activation and debris clearance

Variant: Variants associated with neurodegenerative diseases

Microglia—the brain's immune cells—matter

The convergence point.

Different genes, same result: dopamine neuron death in the substantia nigra. All roads lead to mitochondrial dysfunction, oxidative stress, and protein aggregation.

Why dopamine neurons are vulnerable:

✓Enormous energy demand—long axons, constant firing, calcium handling
✓Dopamine is inherently toxic—oxidizes to reactive quinones
✓High iron content—catalyzes Fenton reactions
✓Limited antioxidant capacity—low glutathione reserves
✓Pacemaker activity—relies on calcium channels that stress mitochondria

The reframe.

The deterministic view

✗Parkinson's is purely genetic
✗If you have the gene, you'll get PD
✗Nothing can be done about genetic risk
✗Environment doesn't matter

The nuanced view

✓Most PD is sporadic—genetics explains only 10-15%
✓Even strong risk genes have incomplete penetrance
✓Lifestyle factors modify genetic risk significantly
✓Pesticides, head trauma, and toxins interact with genes

What actually matters.

These modifiable factors influence PD risk regardless of genetics.

Exercise

The single most protective factor. High-intensity exercise activates BDNF, mitophagy, and dopamine signaling. Forced amplitude exercise (like cycling) may be especially beneficial.

Sleep quality

REM sleep behavior disorder often precedes PD by decades. Sleep is when the brain clears waste proteins including alpha-synuclein via the glymphatic system.

Gut health

Alpha-synuclein pathology may start in the gut and spread to the brain via the vagus nerve. Constipation often precedes motor symptoms by years.

Pesticide exposure

Paraquat, rotenone, and other pesticides are strongly linked to PD risk. They inhibit mitochondrial complex I—same pathway as genetic forms.

Coffee consumption

Consistently associated with lower PD risk. Caffeine is neuroprotective via adenosine A2A receptor antagonism—same target as some PD drugs.

Head trauma

Repeated head injuries increase PD risk. May trigger alpha-synuclein aggregation and neuroinflammation.

Prodromal signs.

These non-motor symptoms often appear years or decades before the classic tremor and movement problems. They represent early alpha-synuclein pathology.

●Loss of smell (anosmia)

●REM sleep behavior disorder

●Constipation

●Depression and anxiety

●Subtle motor changes (small handwriting)

●Shoulder stiffness

Note: Having these symptoms doesn't mean you'll develop PD. Many people with these symptoms never do. But they warrant attention.

The gut-brain axis.

Emerging evidence suggests PD may start in the gut, not the brain.

Braak's hypothesis

Alpha-synuclein pathology may begin in the gut (enteric nervous system) and spread to the brain via the vagus nerve. This explains why constipation precedes motor symptoms.

Vagotomy evidence

People who've had their vagus nerve severed (for ulcer treatment) have significantly lower PD risk—supporting the gut-to-brain transmission theory.

Microbiome differences

PD patients have altered gut bacteria compared to controls—less anti-inflammatory species, more pro-inflammatory. Dysbiosis may trigger or accelerate neurodegeneration.