Neuroprotective properties of the proteasome activator PA28α
- Reference number
- ID21-0018
- Project leader
- Erhardt, Sophie
- Start and end dates
- 230701-280630
- Amount granted
- 2 500 000 SEK
- Administrative organization
- Karolinska Institutet
- Research area
- Life Sciences
Summary
Chronic mental illness (CMI) such as schizophrenia and the neurodegenerative disorders Alzheimer’s and Parkinson’s disease can be characterized by protein mis-assembly and aggregation. Neuronal proteinopathies affect millions of people globally and there is a high degree of unmet clinical need. Mechanisms that protect against protein aggregation are therefore therapeutically interesting and our aim is to modulate targets, important in a range of human neurodegenerative diseases, to reduce the accumulation of protein aggregates. The proteasome activator PA28α has proven protective effects against proteinopathy during embryonic development and potentially therapeutic benefits later in life. Our recently published studies have identified a novel chaperone-like function associated with PA28α (demonstrated by enhanced aggregation prevention in hippocampal extracts) and improved cognitive function (memory and learning) in old mice. These novel findings highlight PA28α as an interesting therapeutic candidate in neurodegenerative research. We aim to determine if increasing levels of neuronal PA28α can counteract the development of CMI and neurodegenerative disorders in established mouse models of human disease. Extensive biochemical, histological and phenotypic analysis will be used to determine whether increased PA28α is protective against (and conversely whether a decrease in protein levels accelerates) protein aggregation, leading to clinical benefit.
Popular science description
Finding new drugs to treat a wide range of the many common brain disorders (which are on the rise due to increased life expectancy) would be easier if they were all different versions of the same disease. Alzheimer’s, Parkinson’s and schizophrenia are among the world’s most common brain diseases and a similar basic defect is common to all three: errors in the body’s ability to fold protein into the correct shape and the subsequent toxic accumulation of these mis-shaped proteins. Current treatments can relieve patient symptoms, but there are no cures. The aim of this study is to find to treatments of these disorders by developing new types of drugs aimed at reducing the amount of mis-shaped protein. We have recently published results showing that when more of a protein called PA28α is made in the brains of mice it can lead to a lower accumulation of badly folded protein. We also found that cognition and memory (which are impaired in Alzheimer’s, Parkinson’s and schizophrenia) were improved in these mice. Our belief is that increased amounts of PA28α can protect against brain disease and given that our previous studies were on mice with normal brains, we now want to perform follow up studies to investigate how increasing the amount of PA28α can affect disease progression in mice engineered to have either Alzheimer’s, Parkinson’s or schizophrenia. We will increase the amount of PA28α in these mice and examine their disease progression to look for evidence of reduced levels of protein misfolding and also their ability to perform well in memory and learning tests. Guided by our findings we are hoping to develop a common treatment for many brain conditions, using new types of drugs which can prevent mis-shaped proteins from accumulating and minimize the harm they do to brain cells.