Cutaneous α-Synuclein and Age Spots in Neurodegeneration: A Systematic Review and Testable Hypothesis

: Recent studies have identified phosphorylated α-synuclein in the skin of individuals with neurodegenerative disease. The levels of this protein in the skin have been correlated with disease severity. This protein has been specifically studied in alpha-synucleinopathies such as Parkinsons' Disease (PD) and Multiple System Atrophy (MSA). Given that skin biopsy studies have often shown high levels of phosphorylated α-synuclein in the neck area, and that other clinical studies have described easily identifiable changes in facial skin features, this systematic review explores whether age spots, which are very common in sun-exposed areas (hands and face), could serve as early indicators of neurodegenerative disease. We performed a systematic review of the literature in three databases (Google, Scopus and Pubmed) following PRISMA guidelines. We used the following keywords: "alpha-synuclein and skin", "alpha-synuclein and skin spots", "alpha-synuclein and solar lentigo", "alpha-synuclein and age spots", "alpha-synuclein and melanocytes", "skin biopsy and synucleinopathies", "skin biopsy and neurodegenerative disease", and "Parkinson's Disease. Eleven studies were identified and included. Based on the study results and preliminary evidence in the literature evaluating the effect of α-synuclein on keratinocytes and melanocytes, we propose that the accumulation of this protein within the skin may produce visible alterations that can be quantified to enable early, noninvasive detection of neurodegenerative disease.