Retromer-dependent lysosomal stress in Parkinson's disease

Abstract

While causative mutations in complex disorders are rare, they can be used to extract a biological pathway whose pathogenicity can generalize to common forms of the disease. Here we begin by relying on the biological consequences of mutations in LRRK2 and VPS35, genetic causes of autosomal-dominant Parkinson's disease, to hypothesize that 'Retromer-dependent lysosomal stress' represents a pathway that can generalize to idiopathic Parkinson's disease. Next, we outline a series of studies that can test this hypothesis, including the development of biomarkers of pathway dysfunction. If validated, the hypothesis can suggest a unified mechanism of disease and might inform future diagnostic and therapeutic investigations. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.

Keywords: LRRK2; Parkinson's disease; VPS35; retromer.

Figure 1.

Retromer-dependent lysosomal stress in Parkinson's disease. (a) Retromer's retrograde pathway is vital for the forward delivery of proteases to the lysosomal via the endosome. Proteins, such as APLP2, can accumulate in the multivesicular body (MVB) in a Retromer-dependent manner where they can be secreted to the extracellular space. (b) PD-associated VPS35 mutations target the retrograde pathway, causing a subtle and specific type of lysosomal stress. Lysosomal stress causes LRRK2 translocation to the lysosomal membranes where it hyperphosphorylates RAB proteins leading to lysosomal dysfunction. Retromer-dependent lysosomal stress should manifest in a lysosomal molecular signature and in a secretion signature.