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Funded Studies

Dissecting the Role of GBA1 and LRRK2 in Regulating the Formation of Lewy Bodies

Study Rationale: A key hallmark of Parkinson’s disease (PD) is the accumulation of alpha-synuclein aggregates inside neurons. These aggregates are known as Lewy bodies (LBs). Although mutations in more than 90 genes have been linked to PD, few are able to initiate the disease process on their own. Instead, many represent risk factors that increase the predisposition to PD. Some of these genes converge on pathways essential to cell maintenance and survival and they likely interfere with neurons’ ability to remove alpha-synuclein aggregates. We therefore propose to examine the role that PD-linked mutations play in regulating alpha-synuclein aggregation and pathology.

Hypothesis: We hypothesize that mutations in PD-genes such as LRRK2 and GBA1 — the two most common genetic risk factors of PD — modulate neurodegeneration by acting at a later stage of pathology development, most likely during the transition from alpha-synuclein aggregation to Lewy body-like inclusions.

Study Design: We will carry out these studies using neurons from mice that have PD-linked mutations in the LRRK2 and GBA1 genes. Using this neuronal system, we will reconstitute the key stages of Lewy body formation and dissect the cellular changes and toxic mechanisms associated with each step along the pathway. We will then investigate how mutations in LRRK2 and GBA1 influence each stage of alpha-synuclein aggregation and Lewy body formation.

Impact on Diagnosis/Treatment of Parkinson’s disease: These studies could lead to new drugs for treating or slowing the progression of familial and sporadic PD. The results could also provide insight into the pathogenesis of familial PD and explain why Lewy bodies are not observed in many people with mutations in Parkin and LRRK2.

Next Steps for Development: The next step would be to validate some of the newly identified targets and pathways and assess the therapeutic potential of targeting these pathways to treat PD.


  • Hilal A. Lashuel, PhD

    Lausanne Switzerland

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