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AriSLA - The Foundation for research on ALS - has been set up to make ALS research investments more effective and efficient, to speed up the clinical research impact e and to provide patients with better care, improved conditions and life expectancy. Its aim is to boost Italian excellencies in basic, clinical and technological research. The Foundation founders are Fondazione Cariplo, Fondazione Telethon, Fondazione Vialli and Mauro and AISLA.

 

 

Focus on protein aggregation: is ALS a prion-like disease?

Focus on protein aggregation: is ALS a prion-like disease?

Epidemiological pattern, focal onset, asymmetrically and orderly spreading of neurodegeneration in ALS and selective vulnerability of MNs inspired in the past decades hypothesis of involvement of an infective agent in a disease pathogenesis, but, despite numerous studies aimed at identification of the ALS-related pathogen, the culprit has so far remained elusive. The idea that the pathogenesis of ALS as well of some other common or rare neurological disorders such as Alzheimer's, Parkinson's or Hungtington Disease, might involve mechanisms resembling prion diseases, recently gained new attention due to a description of prion-like properties of major disease-related proteins, including amyloid β and Tau in AD, ά-syn in PD, Huntington in HD, and SOD1 in ALS.

Protein aggregation-related toxicity is one of the central motifs in the pathology of both prion disease and ALS. A disease causing variant is an aberrantly folded conformer (PrPSc) endowed with infectious potential as capable of inducing misfolding of normal cellular protein (PrPc). Prion conformers are functionally distinct and tend to accumulate in different brain regions and cause different clinical phenotypes. Also, structural restrictions determine the cell susceptibility to prions and are a cause of inter-species barrier. The property of conformational templating and self propagation is not confined to prions, but is also characteristic of proteins that tend to accumulate in major neurodegenerative diseases. Misfolded and aggregation-prone SOD1 has been detected both infALS and in sALS patients tissues. Importantly, these aberrant SOD conformers can impose their conformation to their normal counterparts promote misfolding and aggregates formation. If the prion-type behavior of SOD1 was to be confirmed and shown to have a biological relevance in a disease, this would provide a platform for development of targeted therapeutic interventions.

Most of TDP-43 mutations in fALS are clustered in C terminal domain that is the one required for robust cytoplasmic foci formation and toxicity. These mutations are likely to accentuate intrinsic propensity of a protein to aggregate, accelerating the rate but not changing the mechanism of protein deposition. Recent proteome-wide survey by Cushman et al identified TDP-43 and FUS among the mammalian proteins which contain primary sequences that are predictive of a tendency to acquire prion states in yeast. This putative TDP-43 prion domain coincides with C terminal region "targeted" with most pathogenetic mutations. Also N terminal sequence of FUS displays elevated "prion propensity" while this domain is not a major target of ALS associated mutations and it is still unknown if and to which extent is it important for the protein aggregation predisposition. The potential relevance of the prion-related domains in TDP-43 and FUS in normal physiology, pathologic aggregation, and disease progression is currently debated.

 

Miller et al, 2009 Neurodegeneration. Could they all be prion diseases?

Frost& Diamond 2010 Prion-like mechanisms in neurodegenerative diseases

Cushman et al, 2010 Prion-like disorders: blurring the divide between transmissibility and infectivity

Zhang et al, 2009 Abberant cleavage of TDP-43 enhances aggregation and cellular toxicity

Deng et al., 2010 FUS-immunoreactive inclusions are a common feature in  sporadic and non-SOD1 familial amyotrophic lateral sclerosis

Johnson et al, 2008 A yeast TDP-43 proteinopathy model: Exploring the molecular determinants of TDP-43 aggregation and cellular toxicity

Udan & Baloh, 2011 Implications of the prion-related Q/N domains in TDP-43 and FUS.

Yates et al, 2010 Motor neuron disease: Misfolded wild-type SOD1 may link sporadic and familial ALS.

Bosco et al, 2010 Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS.


 




     
     
     
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