Author(s)
Justin Rosales (student) 1
Meghna Madhavan (student) 1
Manav Govil (student) 1
Audrey Mellan (student) 1
Andrew Li (student) 1
Vasudev Kamath (faculty) 2
Gurjinder Kaur (faculty) 1
Affiliation(s)
1Touro College of Osteopathic Medicine, Middletown NY, United States2Arizona State University, Phoenix AZ, United States
Abstract:
Down Syndrome (DS) is strongly associated with early-onset Alzheimer-type neuropathology and motor dysfunction, yet the molecular drivers of cerebellar dysfunction remain poorly defined. While mitochondrial dysfunction and oxidative stress are implicated in DS and Alzheimer’s disease, their direct relationship to cerebellar pathology is not fully characterized.
This postmortem case-control study analyzed cerebellar tissue from individuals with DS and age-matched controls. Mitochondrial DNA (mtDNA) was isolated, and the copy number was determined using quantitative PCR. Additionally, RNA was isolated, converted to cDNA, and the expression of specific genes was measured by reverse transcription PCR. Mitochondrial transcription factor A (TFAM) and Phosphatase and tensin homolog-induced kinase 1 (PINK1) were evaluated as markers of mitochondrial regulatory signaling and mitochondrial quality control, respectively. Western blot was utilized to assess protein expression of amyloid precursor protein (APP) and glial fibrillary acidic protein (GFAP). Statistical comparisons were performed to determine significant molecular differences.
DS cerebellar tissue demonstrated a statistically significant increase in mtDNA copy number compared with controls, suggesting a compensatory elevation of mtDNA due to mitochondrial distress. TFAM and PINK1 analysis revealed reduced and increased cycle thresholds in DS samples, respectively, indicating dysregulated mitochondrial transcriptional signaling and decreased mitophagy, respectively. Decreased mitophagy supports the compensatory increase in mtDNA in DS. Western blot analysis demonstrated a significant increase in APP and GFAP levels in DS tissue, illustrating an Alzheimer ’s-like pathology and elevated reactive astrogliosis. These markers were normalized against beta-actin expression. These findings collectively support mitochondrial dysregulation and neuroinflammatory activation within the DS cerebellum.
This study provides molecular evidence that cerebellar pathology in DS involves intrinsic mitochondrial dysregulation and neurodegenerative signaling, rather than being solely secondary to cortical disease. By linking disrupted mitophagy to amyloid accumulation and glia activation, this study establishes the cerebellum as a primary site of neurometabolic vulnerability in DS, offering a novel framework for targeted therapeutic intervention.