IMPORTANCEMutations of the glucocerebrosidase gene, GBA1 (OMIM 606463), are the most important risk factor for Parkinson disease (PD). In vitro and in vivo studies have reported that ambroxol increases β-glucocerebrosidase (GCase) enzyme activity and reduces α-synuclein levels. These observations support a potential role for ambroxol therapy in modifying a relevant pathogenetic pathway in PD.OBJECTIVE To assess safety, tolerability, cerebrospinal fluid (CSF) penetration, and target engagement of ambroxol therapy with GCase in patients with PD with and without GBA1 mutations.INTERVENTIONS An escalating dose of oral ambroxol to 1.26 g per day.

Cells respond to endolysosome damage by either repairing the damage or targeting damaged endolysosomes for degradation via lysophagy. However, the signals regulating the decision for repair or lysophagy are poorly characterised. Here, we show that the Parkinson's disease (PD)‐related kinase LRRK2 is activated in macrophages by pathogen‐ or sterile‐induced endomembrane damage. LRRK2 recruits the Rab GTPase Rab8A to damaged endolysosomes as well as the ESCRT‐III component CHMP4B, thereby favouring ESCRT‐mediated repair. Conversely, in the absence of LRRK2 and Rab8A, damaged endolysosomes are targeted to lysophagy. These observations are recapitulated in macrophages from PD patients where pathogenic LRRK2 gain‐of‐function mutations result in the accumulation of endolysosomes which are positive for the membrane damage marker Galectin‐3. Altogether, this work indicates that LRRK2 regulates endolysosomal homeostasis by controlling the balance between membrane repair and organelle replacement, uncovering an unexpected function for LRRK2, and providing a new link between membrane damage and PD.

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Parkinson disease (PD) is the most common neurodegenerative movement disorder. Currently only symptomatic treatments exist for PD, and so the search for potential neuroprotective drug targets is of great importance. Chaperone mediated autophagy (CMA) is one of the key cellular mechanisms in protein homeostasis. Many of the pathogenic pathways thought to be important in PD converge on CMA, thus rendering it an attractive therapeutic target. Areas covered: In this review we discuss current up-to-date knowledge of the molecular mechanisms involved in CMA function and regulation. We go on to discuss the links between CMA and PD including CMA's role in ɑ-synuclein processing, oxidative stress, and mitochondrial function. We finish by exploring the potential benefits of how upregulation of CMA may be beneficial in PD and strategies to achieve this. Expert opinion: Upregulation of CMA is an attractive therapeutic target in PD due to its links with several pathogenic pathways . Currently more knowledge of the mechanisms that regulate CMA is required to allow for the development of specific CMA modulators. However, recent studies demonstrating the role of retinoic acid derivatives and miRNAs in regulating CMA are promising, and indirect upregulation of CMA by modulating other lysosomal pathways may be helpful.