Abstract

A COMPREHENSIVE REVIEW ARTICLE ON “A NEW ERA IN PARKINSON’S DISEASE RESEARCH: SKIN BIOPSY AS A DIAGNOSTIC TOOL & MOLECULAR APPROACHES TO PROTEIN MISFOLDING

M. Janaki*, C. Renuka Thejeshwini, T. Sai Sharvani, G. Sravani, S. Ashraf Begum

ABSTRACT

Parkinson’s disease (PD) is an age-related neurodegenerative disorder defined by progressive motor dysfunction and a heterogeneous constellation of non-motor features. Pathologically, PD and related synucleinopathies are characterised by accumulation and spread of misfolded α-synuclein (α-syn). Two converging advances peripheral tissue biomarkers (notably skin biopsy detection of phosphorylated α-synuclein, p-α-syn) and molecular therapies targeting protein misfolding/proteostasis promise to transform diagnosis, patient stratification, and disease-modifying treatment. Recent multicenter studies report high rates of cutaneous p-α-syn detection in clinically defined synucleinopathies (e.g., >90% detection in large cohorts), supporting excellent sensitivity in selected populations; however, methodological heterogeneity across biopsy site, fixation, antibody choice, and readout (IHC vs seed-amplification assays) requires harmonization before routine clinical use. Seed amplification assays (RT-QuIC/PMCA) applied to skin or CSF improves analytical sensitivity and enables detection of seeding activity. On the therapeutic side, strategies aimed at restoring proteostasis (molecular chaperones such as ambroxol), preventing aggregation (small molecules), enhancing clearance (autophagy enhancers), and immunotherapies (anti-α-syn monoclonal antibodies) have progressed into late preclinical and clinical testing with mixed clinical outcomes to date that emphasize the need for earlier, biomarker-enriched trials. Integrating validated tissue biomarkers (skin p-α-syn, RT-QuIC) with molecularly targeted interventions and harmonized protocols provides the most plausible path to effective disease modification in PD.

Keywords: Parkinson’s disease, ?-synuclein, skin biopsy, phosphorylated ?-synuclein, RT-QuIC, proteostasis, ambroxol, and immunotherapy.