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International audience; Specific extracellular deposits, glial or neuronal inclusions help defining an ever increasing number of neurodegenerative diseases. Deposits or inclusions are aggregates of proteins: Aβ peptide and tau proteins in Alzheimer disease, a-synuclein in Parkinson disease, for instance. The protein that specifically accumulates in a given disease may be modified by a mutation that can increase its aggregability. Most often the sequence of the protein is normal. Misfolding, despite the protein normal sequence, is then considered the cause of the aggregation. The ubiquitin-proteasome system detects and eliminates misfolded proteins from the cell. Almost all the inclusions are indeed labeled by anti-ubiquitin antibodies, but, in neurodegenerative diseases, the system is unable to get rid of them. The large protein aggregates constituting the inclusions are poorly reactive. Their formation has been consi- dered a defense mechanism, protecting the cell against the toxic action of soluble oligomers that are, in that hypothesis, the real toxic agent, neutralized through aggregation. Soluble oligomers of Aβ peptide, tau or a-synuclein,for instance, have indeed been isolated and were shown to be toxic. In the prion hypothesis, the misfolded configuration may be passed from the misfolded to the normal protein by simple contact. There are indeed experimental evidences suggesting that this prion-like mechanism does occur in transgenic rodent models of Aβ, tau or a-synuclein pathology. This might be the explanation of thepropagation of the pathology through connections, observed in many neurodegenerative diseases. There is currently no epidemiological data suggesting a transmission of neurodegenerative diseases, comparable to the transmission of Creutzfeldt-Jakob or other prion diseases. The prion-like mechanisms of protein aggregation observed in the experimental animals or suspected through human neuropathology make that possibility not as remote as previously thought.

Specific extracellular deposits, glial or neuronal inclusions help defining an ever increasing number of neurodegenerative diseases. Deposits or inclusions are aggregates of proteins: Aβ peptide and tau proteins in Alzheimer disease, a-synuclein in Parkinson disease, for instance. The protein that specifically accumulates in a given disease may be modified by a mutation that can increase its aggregability. Most often the sequence of the protein is normal. Misfolding, despite the protein normal sequence, is then considered the cause of the aggregation. The ubiquitin-proteasome system detects and eliminates misfolded proteins from the cell. Almost all the inclusions are indeed labeled by anti-ubiquitin antibodies, but, in neurodegenerative diseases, the system is unable to get rid of them. The large protein aggregates constituting the inclusions are poorly reactive. Their formation has been consi- dered a defense mechanism, protecting the cell against the toxic action of soluble oligomers that are, in that hypothesis, the real toxic agent, neutralized through aggregation. Soluble oligomers of Aβ peptide, tau or a-synuclein,for instance, have indeed been isolated and were shown to be toxic. In the prion hypothesis, the misfolded configuration may be passed from the misfolded to the normal protein by simple contact. There are indeed experimental evidences suggesting that this prion-like mechanism does occur in transgenic rodent models of Aβ, tau or a-synuclein pathology. This might be the explanation of thepropagation of the pathology through connections, observed in many neurodegenerative diseases. There is currently no epidemiological data suggesting a transmission of neurodegenerative diseases, comparable to the transmission of Creutzfeldt-Jakob or other prion diseases. The prion-like mechanisms of protein aggregation observed in the experimental animals or suspected through human neuropathology make that possibility not as remote as previously thought.

RESUME La signification des inclusions intracellulaires est tres variable : marqueurs de certaines des maladies de la proteolyse, qu'elles contribuent a identifier, elles peuvent relever de multiples autres mecanismes, souvent intriques. A titre d'exemples, les donnees actuelles sur la morphologie et la signification des lipofuscines du vieillissement cellulaire, des degenerescences neurofibrillaires et des corps de Lewy et sur celles des granules de Birbeck de l'histiocytose langherhansienne sont analysees. Certaines de ces inclusions peuvent resulter de la mise en jeu a la fois des systemes d'endocytose, de production, de malconformation et d'agregation proteique et de ceux de proteolyse intracellulaire. D'autres constituants cellulaires sont souvent aussi impliques. Enfin les systemes de proteolyse ne paraissent pas essentiellement en cause dans le cas des granules de Birbeck, considerees comme des domaines sous-membranaires du recyclage endosomial. Ils jouerent un role decisif dans l'identification de l'origine langerhansienne de l'histiocytose X.

Forensic examination is often requested when skeletal remains are discovered. Detailed visual observation can provide much information, such as the human or animal origin, sex, age, stature, and ancestry, and approximate time since death. New three-dimensional imaging techniques can provide further information (osteometry, facial reconstruction). Bone chemistry, and particularly measurement of stable or unstable carbon and nitrogen isotopes, yields information on diet and time since death, respectively. Genetic analyses of ancient DNA are also developing rapidly. Although seldom used in a judicial context, these modern anthropologic techniques are nevertheless available for the most complex cases.

Forensic examination is often requested when skeletal remains are discovered. Detailed visual observation can provide much information, such as the human or animal origin, sex, age, stature, and ancestry, and approximate time since death. New three-dimensional imaging techniques can provide further information (osteometry, facial reconstruction). Bone chemistry, and particularly measurement of stable or unstable carbon and nitrogen isotopes, yields information on diet and time since death, respectively. Genetic analyses of ancient DNA are also developing rapidly. Although seldom used in a judicial context, these modern anthropologic techniques are nevertheless available for the most complex cases.