Distinct profiles of LRRK2 activation and Rab GTPase phosphorylation in clinical samples from different PD cohorts.

Despite several advances in the field, pharmacodynamic outcome measures reflective of LRRK2 kinase activity in clinical biofluids remain urgently needed. A variety of targets and approaches have been utilized including assessments of LRRK2 itself (levels, phosphorylation), or its substrates (e.g. Rab10 or other Rab GTPases). We have previously shown that intrinsic kinase activity of LRRK2 isolated from PBMCs of G2019S carriers is elevated, irrespective of disease status. In the present study we find that phosphorylation of Rab10 is also elevated in G2019S carriers, but only those with PD. Additionally, phosphorylation of this substrate is also elevated in two separate idiopathic PD cohorts, but not in carriers of the A53T mutation in α-synuclein. In contrast, Rab29 phosphorylation was specifically reduced in urinary exosomes from A53T and idiopathic PD patients. Taken together, our findings highlight the need for the assessment of multiple complimentary targets for a more comprehensive picture of the disease.

Defining (and blocking) neuronal death in Parkinson's disease: Does it matter what we call it?

Parkinson's disease (PD) is the second most common neurodegenerative disease, comprised of both familial and idiopathic forms, behind only Alzheimer's disease (AD). The disease is characterized, regardless of the pathogenesis, primarily by a loss of DA neurons in the ventral midbrain as well as noradrenergic neurons of the locus coeruleus; however, by the time symptoms manifest, considerable neuronal loss in both areas has occurred. Neuroprotective strategies thus have to be paired with more sensitive and specific biomarker assays that can identify early at-risk patients in order to initiate disease-modifying therapies at an earlier stage in the disease. Complicating this is the fact that multiple forms of cell death mediate the neuronal loss; however, with a common underlying element that the cell death is considered a "regulated" form of cell death, in contrast to an un-controlled necrotic cell death process. In this review we focus our discussion on several categories of regulated cell death in the context of PD: apoptosis, necroptosis, pyroptosis, and autophagic cell death. In clinical studies as well as experimental in vivo models of PD, there is evidence for a role of each of these forms of cell death in the loss of midbrain DA neurons, and specific therapeutic strategies have been proposed and tested. What remains unclear however is the relative contributions of these distinct forms of cell death to the overall loss of DA neurons, whether they occur at different stages of the disease, or whether specific sub-regions within the midbrain are more susceptible to specific death triggers and pathways.

The Future of Targeted Gene-Based Treatment Strategies and Biomarkers in Parkinson's Disease.

Biomarkers and disease-modifying therapies are both urgent unmet medical needs in the treatment of Parkinson's disease (PD) and must be developed concurrently because of their interdependent relationship: biomarkers for the early detection of disease (i.e., prior to overt neurodegeneration) are necessary in order for patients to receive maximal therapeutic benefit and vice versa; disease-modifying therapies must become available for patients whose potential for disease diagnosis and prognosis can be predicted with biomarkers. This review provides an overview of the milestones achieved to date in the therapeutic strategy development of disease-modifying therapies and biomarkers for PD, with a focus on the most common and advanced genetically linked targets alpha-synuclein (SNCA), leucine-rich repeat kinase-2 (LRRK2) and glucocerebrosidase (GBA1). Furthermore, we discuss the convergence of the different pathways and the importance of patient stratification and how these advances may apply more broadly to idiopathic PD. The heterogeneity of PD poses a challenge for therapeutic and biomarker development, however, the one gene- one target approach has brought us closer than ever before to an unprecedented number of clinical trials and biomarker advancements.