Protein aggregation and prionopathies

• Published in: Pathologie biologie (Paris) Vol. 62; no. 3; pp. 162 - 168
• Main Authors: Renner, M., Melki, R.
• Format: Journal Article
• Language: English
• Published: Paris Elsevier SAS 01.06.2014; Elsevier; Elsevier Masson
• Subjects: Aging; Agrégation des protéines; Alpha-synucleinopathies; Alpha-synucléinopathies; Alzheimer; Alzheimer Disease; Alzheimer Disease - prevention & control; Amyotrophic Lateral Sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Autophagy; Biological and medical sciences; Biopolymers; Cerebrospinal fluid. Meninges. Spinal cord; Clinical Trials, Phase II as Topic; Cognitive Sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Drug Evaluation, Preclinical; Endocytosis; Humans; Huntington; Inclusion Bodies; Inclusion Bodies - chemistry; Inclusion Bodies - pathology; Life Sciences; Medical sciences; Mice; Nerve Tissue Proteins; Nerve Tissue Proteins - chemistry; Nervous system (semeiology, syndromes); Neurobiology; Neurodegenerative Diseases; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurofibrillary Tangles; Neurofibrillary Tangles - chemistry; Neurofibrillary Tangles - pathology; Neurology; Neurons and Cognition; Parkinson; Plaque, Amyloid; Plaque, Amyloid - chemistry; Plaque, Amyloid - pathology; Polysaccharides; Polysaccharides - therapeutic use; Prion; Prion Diseases; Prion Diseases - metabolism; Prion Diseases - pathology; Prion Diseases - veterinary; Prions; Prions - chemistry; Protein aggregation; Protein Aggregation, Pathological; Protein Aggregation, Pathological - metabolism; Protein Aggregation, Pathological - pathology; Protein Conformation; Psychology and behavior; Sclérose latérale amyotrophique; Solubility; Tauopathies; Tauopathies; Protein aggregation; Alpha-synucleinopathies; Agrégation des protéines; Amyotrophic lateral sclerosis; Prion; Huntington; Alpha-synucléinopathies; Sclérose latérale amyotrophique; Alzheimer; Parkinson; Aggregation; Nervous system diseases; Central nervous system disease; Degenerative disease; Spinal cord disease; Protein
• ISSN: 0369-8114; 1768-3114
• DOI: 10.1016/j.patbio.2014.01.003

Prion protein and prion-like proteins share a number of characteristics. From the molecular point of view, they are constitutive proteins that aggregate following conformational changes into insoluble particles. These particles escape the cellular clearance machinery and amplify by recruiting the soluble for of their constituting proteins. The resulting protein aggregates are responsible for a number of neurodegenerative diseases such as Creutzfeldt-Jacob, Alzheimer, Parkinson and Huntington diseases. In addition, there are increasing evidences supporting the inter-cellular trafficking of these aggregates, meaning that they are “transmissible” between cells. There are also evidences that brain homogenates from individuals developing Alzheimer and Parkinson diseases propagate the disease in recipient model animals in a manner similar to brain extracts of patients developing Creutzfeldt-Jacob's disease. Thus, the propagation of protein aggregates from cell to cell may be a generic phenomenon that contributes to the evolution of neurodegenerative diseases, which has important consequences on human health issues. Moreover, although the distribution of protein aggregates is characteristic for each disease, new evidences indicate the possibility of overlaps and crosstalk between the different disorders. Despite the increasing evidences that support prion or prion-like propagation of protein aggregates, there are many unanswered questions regarding the mechanisms of toxicity and this is a field of intensive research nowadays. La protéine prion et les protéines qui ont des propriétés de type prion partagent un certain nombre de caractéristiques. Du point de vue moléculaire, ces protéines constitutives s’assemblent en particules protéiques insolubles qui échappent à la machinerie cellulaire de dégradation des protéines à la suite de changements conformationnels. Ces particules s’amplifient par le recrutement de la forme soluble des protéines qui les constituent. Ces agrégats protéiques sont responsables d’un certain nombre de maladies neurodégénératives comme les maladies de Creutzfeldt-Jacob, d’Alzheimer, de Parkinson et de Huntington. De nombreuses évidences soutiennent la propagation de ces agrégats protéiques et suggèrent qu’ils sont « transmissibles » entre cellules. Il existe aussi des données qui montrent que des homogénats de cerveaux d’individus développant les maladies d’Alzheimer ou de Parkinson propagent ces maladies dans des animaux modèles tout comme les homogénats de cerveaux de patients développant la maladie de Creutzfeldt-Jacob. De ce fait, la propagation des agrégats protéiques de cellule à cellule pourrait être un phénomène générique qui contribue à l’évolution des maladies neurodégénératives ce qui pourrait avoir des conséquences importantes dans ces maladies. De plus, alors que la distribution des agrégats protéiques est caractéristique pour chaque maladie, de nouvelles évidences suggèrent un chevauchement/interférence de ces agrégats protéiques dans les différents désordres neurologiques. Malgré les nombreuses évidences qui soulignent l’importance de la propagation de type prion des agrégats protéiques impliqués dans les maladies neurodégénératives, il persiste de nombreuses questions sans réponses concernant les mécanismes à l’origine la toxicité de ces particules qui constitue à présent un domaine de recherche intense.