GB1 / Denali Therap - LARVOL DELTA

Talk #3: Interplay of LRRK2 and GCase in PD-relevant Lysosomal Dysfunction (WPC 2026) - "Variants in LRRK2 and GBA1 represent two of the most common genetic contributors to Parkinson’s disease (PD), yet the molecular interplay between these genes and their shared effects on endolysosomal dysfunction remain poorly understood...Functionally, this variant produces more pronounced deficits in PD-relevant pathways than severe GCase loss-of-function mutations linked to Gaucher disease, effects that are recapitulated in CNS cell models and in human E326K carriers. Together, these findings uncover a mechanistic basis for E326K-associated GCase dysfunction and highlight a bidirectional interplay between LRRK2 and GCase that contributes to lysosomal dysfunction in PD."

CNS Disorders • Gaucher Disease • Genetic Disorders • Metabolic Disorders • Movement Disorders • Parkinson's Disease • LRRK2

Identification of GCase activity modifiers to elucidate genetic drivers of Parkinson’s disease (WPC 2026) - "Furthermore, gene burden analysis of rare, predicted LoF variants from 4 independent PD case-control whole exome sequencing datasets revealed dysregulated GCase activity as a major node of PD genetic risk. Taken together, our work uncovers genetic modulators of GCase activity, providing a framework to investigate how these genes may influence the penetrance of GBA1 mutations and contribute to genetically-driven reductions in GCase activity in sPD."

CNS Disorders • Movement Disorders • Parkinson's Disease • GBA • GBA1

Topic #1: GBA1 and LRRK2: what’s the link? (WPC 2026) - "From a therapeutic perspective, we will explore how understanding this relationship can be translated into pathway biomarkers to assess benefits on lysosomal function in the clinic and into supporting patient selection and stratification for LRRK2 and GCase-focused therapies. We will discuss the gaps in our understanding and what we as a field can do to address them."

LRRK2

IDENTIFICATION OF GCASE ACTIVITY MODIFIERS TO ELUCIDATE GENETIC DRIVERS OF PARKINSON'S DISEASE (ADPD 2026) - "Taken together, our work uncovers genetic modulators of GCase activity, providing a framework to investigate how these genes may influence the penetrance of GBA1 mutations and contribute to genetically-driven reductions in GCase activity in sPD."

CNS Disorders • Movement Disorders • Parkinson's Disease • GBA • GBA1

DYSREGULATION OF LYSOSOMAL AND AUTOPHAGIC-ASSOCIATED PROTEINS IN PBMCS AND PLASMA FROM PARKINSON'S DISEASE PATIENTS (ADPD 2024) - "Reduced LAMP1 levels in PD patient supports the hypothesis that lysosomes are reduced in PD patients. Additionally, elevated CatB levels in plasma suggests dysregulation in the normal lysosomal pathway in PD patients. We confirmed prior reports of elevated GCase activity in LRRK2 carriers, which may be biologically meaningful considering reduction of GlcSph."

Clinical • CNS Disorders • Movement Disorders • Parkinson's Disease • CTSB • GBA • LAMP1 • LRRK2