The International Parkinson and Movement Disorders Society (MDS) 2026 Congress featured significant research on genetic forms of Parkinson's disease (PD), with particular emphasis on GBA LRRK2 VPS35 variants. This summary captures the key findings and their implications for understanding PD pathogenesis and therapeutic development.
**Key Takeaways**
Topic
Key Points
GBA 2-5x increased PD risk; rapid progression; therapeutic target in development
LRRK2 Most common genetic cause; kinase inhibitors in clinical trials
VPS35 Autosomal dominant; endosomal trafficking dysfunction
Polygenic Risk Growing recognition of polygenic contribution to idiopathic PD
Research presented at MDS 2026 highlighted several important findings regarding GBA variants:
Risk Association : GBA variants remain the strongest genetic risk factor for PD, increasing risk 2-5x depending on variant severityPhenotype : GBA-PD patients show earlier onset, more rapid progression, and higher prevalence of cognitive impairmentProgression : Certain variants (including severe mutations like N370S) are associated with faster motor and cognitive decline
GBA Modulators : Small molecule GBA activators in developmentSubstrate Reduction Therapy : Targeting glucosylceramide accumulationGene Therapy : AAV-mediated GBA delivery approaches
LRRK2 remains a major focus of PD research:
Prevalence : LRRK2 variants account for ~5% of familial PD and ~3% of sporadic PDPathogenic Mechanisms : LRRK2 kinase hyperactivity leads to neuronal dysfunction through multiple pathwaysAnimal Models : New LRRK2 knock-in models showing relevant phenotypes
The LRRK2 field has made significant progress:
Drug
Target
Status
Company
DNL151
LRRK2 inhibitor
Phase 2
Denali
BIIB122
LRRK2 inhibitor
Phase 2
Biogen
LJ1891
LRRK2 inhibitor
Phase 1
Ludwig Institute
VPS35 research presented at MDS 2026 emphasized:
D620N Mutation : The most common pathogenic VPS35 variant causes autosomal dominant PDEndosomal Dysfunction : VPS35 mutations impair retromer function, leading to protein trafficking abnormalitiesAlpha-Synuclein Connection
Retromer Stabilizers : Small molecules enhancing VPS35 functionProtein-Protein Interaction Inhibitors : Blocking abnormal protein interactions
Research highlighted several additional genetic contributors:
SNCA : Alpha-synuclein gene duplications/triplicationsPRKN : Parkin mutations (early-onset PD)PINK1 : Mitochondrial quality controlDNAJC13 : Endosomal traffickingGBA2 : Related to GBA pathway
The polygenic nature of PD was emphasized:
Genome-Wide Studies : Large GWAS have identified >90 risk lociPolygenic Risk Scores : PRS show promise for identifying at-risk individualsGene-Environment Interaction : Increasingly recognized
Who to Test : Young onset, family history, specific phenotypesTesting Benefits : Prognosis, family counseling, clinical trial eligibilityChallenges : Variant interpretation, incidental findings
Targeted Therapies : Genetic stratification for clinical trialsDisease Modification : Potential for mutation-specific interventionsNeuroprotection : Early intervention based on genetic risk
Natural History Studies : Understanding progression in genetic formsBiomarker Development : Tracking disease progressionTherapeutic Trials : Gene-specific and mutation-specific approachesCombination Therapies : Targeting multiple pathways
Plenary sessions on genetic forms of PD
Poster sessions on new genetic discoveries
Workshops on genetic counseling
Industry-sponsored symposia on therapeutics