Title of project or programme

Cellular aspects of protein misfolding in neurodegenerative diseases

Principal Investigators of project/programme grant
Title Forname Surname Institution Country
Dr Anne Bertolotti MRC Laboratory of Molecular Biology UK
Address of institution of lead PI
Institution MRC Laboratory of Molecular Biology
Street Address Hills Road
City Cambridge
Postcode CB2 0QH
Country
  • United Kingdom
Source of funding information

Medical Research Council

Total sum awarded (Euro)

1474202.39

Start date of award

01-04-2006

Total duration of award in months

48

The project/programme is most relevant to
  • Huntington’s disease
Keywords
Research abstract in English

Aggregation of misfolded proteins is a characteristic of several neurodegenerative diseases. The huntingtin amino-terminal fragment with expanded polyglutamine repeat (polyQ) aggregates both in the cytoplasm and the nucleus. We recently discovered that aggregation of a protein containing a polyQ stretch of pathological length is abolished when its expression is targeted to the endoplasmic reticulum or mitochondria. Preventing aggregation of a paradigmatic aggregation prone protein while achieving high levels of expression is a striking finding. Our data imply that polyQ aggregation is a property restricted to the nucleo-cytosolic compartment and suggest the existence of compartment-specific co-factors promoting or preventing aggregation of pathological proteins. We have not ruled out the existence of anti-aggregation factors preventing polyQ aggregation in the ER and the mitochondria, but we have recently identified a nucleo-cytosolic aggregation enhancer. While it is clear from in vitro studies that aggregation propensity of pure polyQ peptides is extremely high, in inclusions of Huntington s disease patients, Huntingtin amino-terminal fragments contain additional sequences. The polyQ expansion in Huntingtin is immediately followed by a proline-rich region and we found that this region strongly antagonizes aggregation. Thus, in the context of the amino-terminal fragment of Huntingtin, some trigger ought to be required to alleviate this inhibition and convert the soluble protein into an aggregation-prone one. We found that while a protein needs to be unfolded to be degraded, uncoupling unfolding and degradation promotes accumulation of aggregation-prone folding intermediates. We propose that uncoupling unfolding and degradation triggers misfolding of mutant Huntingtin. This uncoupling event might also be involved in other neurodegenerative diseases, an hypothesis we are currently testing. Indeed, several lines of evidence indicate that different neurodegenerative diseases might arise from a common molecular mechanism. Seeking further experimental support for this model, we have undertaken to analyze the effect of specific chemical compounds curing yeast Prions in cellular models of Huntington’s disease and found 2 active compounds, one of them being a marketed drug. These compounds might define a new class of anti-amyloidogenic-proteins compounds because they do not act directly on the aggregates but might rather enhance clearance of the soluble pathogenic fragment of Huntingtin. We are continuing to explore the cellular pathway responsible for this effect. Identification of a cellular pathway enhancing the cell s ability to remove abnormal proteins might have some therapeutic benefit.

Lay Summary

    Principal Investigators

    Dr A Bertolotti

    Institution

    MRC Laboratory of Molecular Biology

    Contact information of lead PI

    Country

    United Kingdom

    Title of project or programme

    Cellular aspects of protein misfolding in neurodegenerative diseases

    Source of funding information

    MRC

    Total sum awarded (Euro)

    € 5,343,592

    Start date of award

    14/08/2011

    Total duration of award in years

    5.0

    The project/programme is most relevant to:

    Neurodegenerative disease in general

    Keywords

    Protein folding| stress responses| SOD1| polyglutamine| neurodegenerative diseases

    Research Abstract

    The deposition of misfolded proteins is the hallmark of the late onset, rapidly progressive and devastating neurodegenerative diseases including Alzheimer’s, Parkinson’s, Huntington’s and amyotrophic lateral sclerosis. These diseases are caused by a gain of toxic properties associated with the propensity of otherwise soluble proteins to misfold. Neurodegenerative diseases usually strike in mid-adult life, while the disease-causing proteins are expressed throughout the entire life implying that these misfolded-prone proteins are actually benign for decades. What governs the switch from the soluble and harmless conformation to a misfolded and deleterious one is unclear. We are aiming at understanding what triggers this pathological conformational switch as it is one of the earliest events in the etiology of neurodegenerative diseases. We have recently discovered that mutant SOD1 aggregates, associated with amyotrophic lateral sclerosis, penetrate inside cells and replicate their misfolded state indefinitely, just like prions. Using a combination of approaches and mole systems, we are aiming at identifying the mechanisms underlying the prion-like propagation of misfolded proteins. In addition, we aim at identifying novel strategies that could lead to correct conditions caused by misfolded proteins. Recently, have discovered a novel and selective way to rescue cells from stress caused by misfolded proteins. We have identified a small molecule, guanabenz, which binds to a regulatory subunit of protein phosphatase 1, PPP1R15A/GADD34, selectively disrupting the stress-induced dephosphorylation of the alpha subunit of translation initiation factor 2 (eIF2). Without affecting the related PPP1R15B-phosphatase complex and constitutive protein synthesis, guanabenz prolongs eIF2 phosphorylation in stressed cells, thereby adjusting the protein production rates to levels manageable by available chaperones. This favours protein folding and thereby rescues cells from protein misfolding stress. This suggests that inhibition of PPP1R15A could ameliorate protein misfolding diseases. We will est this attractive possibility. In addition, having provided the proof of principle that serine/threonine phosphatases are drug targets, we aim to investigate the detailed molecular mechanism by which guanabenz selectively inhibits PPP1R15A/GADD34, using a combination of approaches Ultimately, the knowledge emanating from our work will serve to ameliorate human health and disease.

    Lay Summary

    Alzheimers disease, Parkinsons disease, Huntingtons disease, amyotrophic Lateral Sclerosis (ALS) and Prion disease are devastating and affect an increasing number of individuals in the ageing population. These neurodegenerative diseases are of immense medical and socioeconomic significance worldwide, as no treatments exist so far. Each neurodegenerative disease is caused by the progressive dysfunction and death of specific nerve cells in selective regions of the brain due to the accumulation of a specific protein of aberrant shape. The disease causing proteins are very diverse but all share a common property: they are soluble and benign for decades but misfold and assemble in amyloid-like deposits in aged neurons. This suggests that the molecular mechanisms at the origin of the diverse neurodegenerative diseases may be shared. my long-term goal is to understand the prion-like propagation of misfolded proteins and to identify strategies that could lead to cure protein misfolding.

    Further information available at:

Types: Investments > €500k
Member States: United Kingdom
Diseases: Huntington's disease
Years: 2011
Database Categories: N/A
Database Tags: N/A

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