Clinical Proteomics and Molecular Neuropathology in the Skotte Group

The focus of the Skotte Group is to explore protein alterations in Huntington’s disease to discover new biomarkers using human biofluids and to define novel drug targets using human induced pluripotent stem cells as well as murine single cell populations, including neurons, astrocytes, microglia, and oligodendrocytes, from the central nervous system.

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by loss of voluntary motor control, psychiatric disturbances, and cognitive decline. There is currently no therapy available that can delay onset or slow HD progression. The mutant huntingtin protein causes neuropathology with striatal volume reduction and cortical thinning starting more than a decade before symptoms. The basis of the selective neuronal vulnerability leading to degeneration and loss of specific brain regions, cell types, and synaptic connections in HD remains elusive.

The vision is to develop predictive biomarkers for disease progression and treatment response to enable clinical trials using human biofluids and to explore and identify novel avenues for therapeutic strategies based on insights from proteomic analysis of specific cell types in the healthy and disease brain. Selective neuronal vulnerability is not unique to HD and defines disorders such as Parkinson’s disease, Alzheimer’s disease, Amyotrophic Lateral Sclerosis, and spinocerebellar ataxia. Hence, valuable lessons learnt from HD research may apply to other neurodegenerative disorders.

1. Temporal and regional analysis of the diseased brain brings insights into Huntington’s disease pathogenesis and progression.

2. Combinatorial therapeutic strategies to improve glial homeostasis may help ameliorate symptoms and protect neurons in Huntington’s disease.

3. One hundred altered proteins in biofluids from Huntington’s disease patients, which may pave the way for new clinical biomarker candidates.