Harnessing the mitochondrial vulnerability of neurons from Huntington´s disease patients for uncovering novel therapeutic targets

• Applicant: Professor Alessandro Prigione, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 555130237

Expansion of the glutamine tract (poly-Q) in the protein Huntingtin (HTT) causes the neurodegenerative disorder Huntington’s disease (HD). Emerging evidence suggests that mutant HTT (mHTT) disrupts brain development. To gain mechanistic insights into the neurodevelopmental impact of human mHTT, we previously engineered induced pluripotent stem cells (iPSCs) to introduce mutant 70Q expansion or to remove the poly-Q tract of HTT. We found that 70Q introduction caused aberrant development of cerebral organoids with loss of neural progenitor organization. The early neurodevelopmental signature of mHTT highlighted the dysregulation of the protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), a transcription factor involved in mitochondrial integrated stress response. CHCHD2 repression was associated with abnormal mitochondrial morpho-dynamics and function. Elimination of the poly-Q tract of HTT normalized CHCHD2 expression and mitochondrial defects. Hence, our current results suggest that mHTT-mediated disruption of human neurodevelopment is paralleled by aberrant neurometabolic programming mediated by dysregulation of CHCHD2, which could then serve as an early interventional target for HD. We now propose to investigate in more details the mechanistic role of CHCHD2 in the pathogenesis of HD and its impact on human neurodevelopment. We propose to address the following questions: (i) are neurodevelopmental defects and CHCHD2 impairment occurring within striatal brain cells and medium spiny neurons that are known to be particularly impaired in HD patients? Can this be recapitulated in both engineered cells and patient-derived cells? (ii) What are the downstream consequences of CHCHD2-mediated defects on the structure and functionality of mitochondria within developing brain cells? (iii) Can CHCHD2 represent a target of intervention? And what are its mechanistic partners and regulators? To address these issues we will employ regionalized striatal brain organoids that we have demonstrated to express medium spiny neurons, which are the brain cells specifically impaired in HD. We will use both engineered iPSC lines and patient-derived lines. We will take advantage of several technologies, including single-cell transcriptomics, advanced imaging analyses, biochemistry and functional and metabolic assessments. Our data will elucidate the impact of mHTT on human striatal-specific neurodevelopment and on the related mitochondrial and metabolic programming, and could uncover a novel causative role for CHCHD2 dysregulation in the pathogenesis of HD. These findings may thus unveil innovative targets of intervention for a detrimental neurological disease.

• DFG Programme: Research Grants