Research Projects

Parkinson’s Disease (PD) and Multiple System Atrophy (MSA) are progressive synucleinopathies with overlapping motor symptoms, making early and accurate diagnosis challenging. α-Synuclein (α-syn) aggregates, particularly it’s phosphorylated form (pS129) are central to the pathology of synucleinopathies. In PD, it forms Lewy bodies and Lewy neurites in neurons, while in MSA, it deposits as glial cytoplasmic inclusions (GCIs) in oligodendrocytes (Wakabayashi K et al.1998; Majbour NK,et al.2016). Currently the MSA diagnosis relies on clinical and radiological assessments, with confirmation possible only through autopsy after death, making early and accurate diagnosis difficult (Wenning GK et al. 2022). MSA is more aggressive, and misdiagnosis affects prognosis and delays treatment. Attempts to develop imaging and cerebrospinal fluid-based biomarkers for synucleinopathies have not translated to regular clinical practice as they are invasive or lack specificity (Shahnawaz M, et al. 2020). Blood-based biomarkers offer a non-invasive alternative but has challenges like plasma protein contamination and low central nervous system (CNS) biomolecules. Recently, CNS specific exosomes-based biomarkers from blood have emerged as a promising candidate, as they cross the blood-brain barrier and carry disease-specific α-syn species, potentially reflecting CNS pathology more accurately (Shi et al.2014). α-syn aggregates is central to MSA and PD pathology, making it a primary candidate for biomarker development (Dutta et al. 2021). The distinct accumulation of α-syn, particularly pS129, in neurons in PD and oligodendrocytes in MSA makes its exosomal form a promising tool for differential diagnosis (Yu et al. 2020; Jiang et al. 2020). Despite studies reporting elevated pSyn-129 in blood-derived exosomes, its cell-type specific expression in neuronal and oligodendrocyte remains unexplored in India. We propose to develop a reliable, validated, and less-invasive blood-based biomarker for differential diagnosis of MSA and PD by analyzing brain cell-specific markers in patients and healthy controls. We will use FACS for isolating L1CAM-positive putative neuronal exosomes and MOG-positive putative oligodendroglial exosomes. Then we will investigate it’s pSyn-129, total α-syn, and other markers (Dutta et al. 2021). Unlike previous studies, we aim to re-validate key findings (e.g., pSyn-129) using specific cell types differentiated from healthy control and patient-derived iPSCs from a subset of the same patients. This approach allows us to model disease, validate biomarkers, enhancing their reliability using iPSCs, a human-relevant system, when brain tissue is unavailable. The rationale of the study is to develop blood based differential diagnostic biomarkers for PD and MSA and to validate our candidate biomarkers using iPSCs. These biomarkers could aid early diagnosis, guide treatment, and deepen our understanding of disease mechanisms.