Disease mechanisms
Alpha-synuclein aggregation, mitochondrial dysfunction, lysosomal dysfunction, gut-brain axis, neuroinflammation, oxidative stress, iron / ferroptosis, calcium dysregulation and the other biological pathways linked to Parkinson's.
In this category
- Alpha-synuclein biology
- Blood-brain barrier
- Calcium dysregulation
- Dopamine metabolism & DOPAL
- Glutamate excitotoxicity
- Gut-brain axis
- Iron & ferroptosis
- Lysosomal dysfunction & autophagy
- Mitochondrial dysfunction
- Neuroinflammation
- Oxidative stress
- Synaptic & vesicular dysfunction
- Ubiquitin-proteasome system
State of the art
No update yet for Disease mechanisms. An update is a standalone state-of-the-art for the topic — what someone with Parkinson's needs to know about where this approach stands today.
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Exercise and smoking: health rivals revealing shared protective mechanisms in Parkinson’s? Neuroinflammation
The paper identifies suppression of neuroinflammation (microglial activation and peripheral immune signalling) as one of the shared protective mechanisms activated by both exercise and certain tobacco compounds, positioning it as a key target for future disease-modifying drug development. -
Levodopa increases substantia nigra iron: implications for Parkinson's disease Iron & ferroptosis
This preprint adds to evidence that levodopa treatment itself may increase iron accumulation specifically in the substantia nigra — not just PD pathology alone — suggesting the drug could contribute to the oxidative and ferroptotic stress it is meant to work around. -
Superior dorsal nigral hyperintensity depiction at 7 T MRI using CLEAR-DESS improves diagnosis performance of Parkinson’s disease Iron & ferroptosis
The head-to-head comparison between iron-sensitive SWI and the iron-suppressing CLEAR-DESS sequence at 7T MRI provides indirect in-vivo evidence that iron accumulation in the substantia nigra, while detectable, is not the optimal contrast mechanism for diagnosing PD: neuromelanin/free-water contrast captured by CLEAR-DESS gave markedly higher diagnostic accuracy. -
Observations on an Open‐Label Phase 1/2 Dopamine Gene Therapy Trial (OXB‐102/Axo‐Lenti‐PD) in People with Parkinson's Disease Dopamine metabolism & DOPAL
Demonstrates in a human surgical setting that non-dopaminergic striatal neurons can be reprogrammed via lentiviral delivery of TH, GCH1, and AADC to synthesise dopamine continuously from endogenous tyrosine, bypassing the degenerating nigrostriatal pathway — a proof-of-concept for continuous enzymatic dopamine replacement at the site of depletion. -
Genome-wide association and population-tailored polygenic risk for Parkinson’s disease in Taiwan Mitochondrial dysfunction
A suggestive GWAS signal at PPARGC1A (rs609501; OR 1.22; P=3.5×10⁻⁶) — encoding PGC-1α, a master regulator of mitochondrial biogenesis — nominates this locus as a Taiwan-relevant PD risk factor, supported by prior rare-variant data in Han Chinese and epidemiological evidence linking the PPARγ agonist pioglitazone to lower PD incidence in Taiwan. -
Region-specific cortico-striatal transcriptomic remodeling following early postnatal dopaminergic disturbance Dopamine metabolism & DOPAL
A mouse study using early postnatal 6-OHDA (the same dopamine-depleting neurotoxin used in adult PD models) found 369 gene-expression changes in the prefrontal cortex and 493 in the striatum, with region-specific patterns: cortical changes reflected developmental and signalling programs, while striatal changes reflected locomotor regulation, extracellular matrix organisation, and amphetamine response. The results provide a gene-level map of how dopamine loss reshapes corticostriatal molecular programs — relevant to understanding why circuits fail in PD. -
Co‐ and Multi‐Pathologies in Parkinson's Disease: An International Parkinson and Movement Disorder Society Scientific Issues Committee Review Co-pathologies in PD
This MDS Scientific Issues Committee review establishes the conceptual framework of co-pathologies (one additional pathology) and multi-pathologies (several at once) as the norm — not the exception — in PD brains, identifying Alzheimer-type changes, cerebrovascular disease, and TDP-43 deposits as the most prevalent companions to Lewy body pathology and arguing that the specific mix largely determines each patient's individual disease course. -
Cerebellar Network Compensation in Parkinsons Disease: Functional Connectivity Across Motor and Cognitive Circuits Cerebellar network compensation
This cross-sectional fMRI study of 172 PPMI participants provides the most direct evidence to date that the cerebellum actively reorganises its connections with the basal ganglia and cortex in PD — with enhanced Crus I–motor cortex coupling in cognitively normal patients that is absent in those with cognitive decline. The findings support "cerebellar reserve" as a distinct mechanism: the cerebellum lending resources to maintain function when dopaminergic circuits fail, with that reserve diminishing as the disease progresses. -
Parkinson : une voie cérébrale protège les neurones féminins - Daily Beirut Neuroinflammation
The Texas A&M mouse study found that genetically boosting β2-containing nicotinic acetylcholine receptors in dopaminergic neurons reduced apoptotic (cell-death) signalling and ER stress — a cellular stress pathway linked to neuroinflammation — but only in females, suggesting sex-specific differences in how these protective circuits operate at the molecular level. -
Myelin damage in donor skin differentiates between synucleinopathies
By quantifying myelin sheath fragmentation and swellings in over 1,100 peripheral nerve axons from donor skin, the study shows that PD — but not MSA — is associated with elevated damage to the peripheral myelin-axon unit, indicating that PD pathology extends to peripheral nerve integrity in a disease-specific way that differs from a closely related synucleinopathy. -
Safety and efficacy of faecal microbiota transplantation in Parkinson’s disease Gut-brain axis
The review provides the most comprehensive human-trial summary to date of attempts to intervene on the gut-brain axis in Parkinson's via FMT, finding that gut microbiome composition does shift after transplant (most consistently an increase in Firmicutes), but that these shifts have not yet translated into reliable clinical benefit for motor or most non-motor symptoms in controlled trials. -
Démence à corps de Lewy : voici pourquoi elle est confondue avec Parkinson et Alzheimer (et ce que ça change) - Cap Retraite Alpha-synuclein biology
The article explains to a lay audience that LBD and Parkinson's share the same underlying pathological process — abnormal alpha-synuclein aggregates forming Lewy bodies inside neurons — which is why the two diseases overlap clinically and why treatments effective or safe in one may not be in the other. -
'Garbage collectors' of the brain grind to a halt in fatal multiple system atrophy Neuroinflammation
A post-mortem single-nucleus RNA sequencing study of 117,000+ brain cells found that microglia in MSA patients are exhausted and functionally inactive in late-stage disease — the opposite of the microglial overactivation seen in Parkinson's. The researchers propose that early immune overactivation leads to burnout, leaving the brain unable to clear toxic waste, which may explain MSA's faster progression compared to Parkinson's. -
Prebiotics balance gut bacteria and show results in Parkinson’s blood Gut-brain axis
The study provides first-in-kind evidence that extracellular vesicles in blood carry both human and bacterial proteins that reflect gut-microbiome composition in Parkinson's, and that correcting dysbiosis with prebiotics normalises these circulating signals — adding a mechanistic link between gut-barrier integrity, immune activation, and the gut-brain axis in PD. -
The biological clock in parkinson’s disease: mechanisms and chronotherapy
This review consolidates the case that circadian (24-hour body-clock) disruption is a driver of Parkinson's progression, not merely a downstream symptom — citing evidence that clock genes influence dopamine-neuron survival, alpha-synuclein clearance, and neuroinflammation, while PD pathology in turn damages the brain regions that keep time. It positions chronobiology alongside alpha-synuclein and mitochondrial dysfunction as a mechanism worth targeting. -
Allergic disease as a risk factor for Parkinson’s disease: a possible role of eosinophil
This study provides population-scale evidence that chronic allergic inflammation — particularly from asthma and allergic rhinitis — is associated with increased PD incidence, supporting the idea that immune-driven neuroinflammation is a meaningful contributor to PD pathogenesis. The dose-response pattern (more severe allergy = higher risk) strengthens the biological plausibility of a causal inflammatory link. -
Parkinson's Disease.
The article frames Parkinson's as a multisystem alpha-synucleinopathy in which abnormal aggregation of alpha-synuclein protein spreads through the nervous system well before motor symptoms emerge. It underscores that dopamine-neuron loss in the substantia nigra is a late event in a longer biological cascade, reshaping how both diagnosis and future treatment should be timed. -
Driving motor cortex oscillations restores plasticity and improves bradykinesia features in Parkinson’s disease
The study demonstrates that impaired GABA-A inhibitory signalling and lost motor cortex plasticity are directly linked to bradykinesia severity in Parkinson's, and that correcting the gamma rhythm mechanistically rescues both — strengthening the causal chain between cortical oscillation deficits and slowed movement. -
Preformed fibrils of α-synuclein rapidly activate LRRK2 on early endosomes, driving Rab5 phosphorylation and disrupting endolysosomal and synaptic function
This article maps a precise molecular chain — alpha-synuclein clumps → rapid LRRK2 activation on early endosomes → Rab5 disruption → lysosomal failure → gene expression shutdown — showing for the first time that early endosomes act as a central hub connecting protein aggregation to nuclear and synaptic damage in PD neurons.