Proteasome complexes and mitochondrial dynamics in neurodegeneration
Principal Investigator:
Krisztina Tar, Ph.D, associate professor (tark@med.unideb.hu)
Current lab members:
Hossameldin Ali, PhD student
Yulia Zaikina, TDK student
Yonatan Adiniaev, TDK student
Davies Michelle Tamunobelema, TDK student
Eylül Salso, TDK student
Karolina Kovács, laboratory assistant
Current projects:
The contribution of gastrointestinal motility changes to weight loss in patients with Huntington’s Disease.
Exploring the role of the proteasome activator PA200 in the decreased fertility of Huntington’s Disease (HD) transgenic male mice.
The non-canonical role of the proteasome activator PA200.
Summary of research:
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation—a CAG trinucleotide expansion repeat—in the first exon of the huntingtin gene (HTT). HD affects both the central nervous system (CNS) and non-neuronal tissues because the HTT gene is expressed ubiquitously.
While the molecular mechanisms and CNS effects have been well studied, the impacts on peripheral tissues remain poorly understood. Most research on HD focuses on the central nervous system, yet the mutant huntingtin protein is widely expressed throughout the body. Thus, the disorder also involves systemic effects. One important non-neurological symptom of HD is weight loss, which may be due to altered gastrointestinal (GI) motility. However, intestinal dysmotility in HD is the least studied among neurodegenerative diseases, and the likely diversity of underlying mechanisms is poorly understood. Therapeutic interventions are necessary to alleviate GI symptoms.
Based on our data, we hypothesize that alterations in the enteric-nervous system (ENS)-intestinal smooth muscle axis contribute to GI dysfunction, leading to weight loss in patients with HD. Our goal is to unravel the biomolecular and neurochemical changes underlying GI dysfunction in HD mice (R6/1, HDexon1). We functionally characterize intestinal smooth muscle contractility and analyze morphological changes in the ENS in HD using an ex vivo organ bath, functional and biochemical assays, and immunohistochemistry (IHC) in collaboration with the groups of Drs Karen Uray and Péter Szűcs (Department of Anatomy). Identifying the mechanism underlying GI deficiencies will help identify therapeutic interventions to help patients avoid weight loss and improve their quality of life.
Figure 1. HD mice exhibit significant weight loss compared to wild-type (WT) mice.
PA200 is an alternative proteasome activator found in all mammals. It mediates ATP- and ubiquitin-independent degradation of unstructured proteins and acetylated histones. PA200 is present in all mammalian tissues and is highly expressed in testes. It is well established that PA200 is necessary for normal spermatogenesis in mice, indicating that the proper production of male gametes requires specific protein metabolic processes. Homozygous PA200 knockout mice are infertile.
According to the literature, the initial reproductive capacity is usually not directly affected in HD patients; it is mainly the huge dilemma that arises after testing positive for HD.
Our HD transgenic mouse model, however, shows a phenotype characterized by reduced fertility and impaired proteasome composition. Our data suggest that spermatoproteasome-dependent protein degradation is disrupted, leading to reduced fertility in male HD mice. We aim to elucidate the underlying molecular mechanisms by applying biochemical and microscopic assays.
Figure 2. H&E staining shows disrupted testicular morphology in HD mice compared to healthy wild-type (WT) mice
List of publications:
https://pubmed.ncbi.nlm.nih.gov/?term=krisztina+tar&sort=date&sort_order=desc
https://scholar.google.com/citations?user=eSpA7A8AAAAJ&hl=en&oi=ao
https://tudoster.unideb.hu/hu/szerzok/3296