Trinucleotide repeats and neurodegenerative disease

Abstract

Major insights have been attained into the molecular pathology of the trinucleotide repeat neurodegenerative diseases over the past decade. Genetic definition has allowed subclassification into translated polyglutamine diseases, which are due to CAG repeat expansions, and a more heterogeneous group in which the trinucleotide repeat remains untranslated. The polyglutamine disorders are due to a toxic gain of function of mutant expanded proteins. Neuronal intranuclear inclusions (NIIs) characteristically occur. Protein misfolding, interference with DNA transcription and RNA processing, activation of apoptosis and dysfunction of cytoplasmic elements have all been invoked in the toxic process. The end result is apoptotic cell death with many aspects of neuronal function being perturbed. Promising progress has been made into arresting and reversing neurodegeneration in both cellular and animal models. The molecular mechanisms underlying the untranslated group remain less clear. Impedance of gene transcription secondary to abnormal DNA structures formed by repeats, modification of chromatin gene packaging and dysfunction at the RNA level have all been suggested as possible pathological mechanisms. These diseases remain irreversible. It is hoped that clarification of the molecular pathogenic mechanisms will provide the tools for future therapeutic intervention.

Spinocerebellar ataxias

“…SCA 2 is characterized by cerebellar ataxia with dysarthria, tremor, hyporeflexia/deep areflexia of the upper and lower limbs (defining the presence of associated peripheral neuropathy), fasciculations of the face and limbs, and characteristic slow saccadic eye movements [3][4][5][6][7][8][9][10] .…”

“…Cognitive deficits have been described in patients with SCA 2 with a frequency of 5 to 19% 46 . SCA 2 is characterized by cerebellar atrophy with a loss of Purkinje and granular cells, olivary neurons, substantia nigra and cells in the anterior horn of the spinal cord [3][4][5][6][7][8][9][10] .…”

“…SCAs are clinically characterized by the presence of cerebellar gait and limb ataxia (with dysmetria, dysdiadochokinesia, intention tremor, dysarthria and nystagmus), which may be accompanied by extracerebellar signs such as ophthalmoplegia, pyramidal signs, movement disorders (including parkinsonism, dystonia, myoclonia and chorea), dementia, epilepsy, visual disorders (including pigmentary retinopathy), lower motor neuron disease and peripheral neuropathy [1][2][3][4][5][6][7][8][9][10] .…”

Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex

“…Expanded CAG sequences are translated into elongated polyglutamine (polyQ) stretches. This renders the respective proteins insoluble and leads to the formation of protein aggregates [2][3][4][5][6][7] .…”

Modèles animaux des maladies neuro-dégénératives

“…Plusieurs souris transgéniques SCA ont été produites, notamment la souris SCA7 chez laquelle l'ataxie est associée, comme chez l'homme, à une rétinite pigmentaire et à des inclusions nucléaires [41]. Le rôle physiopathologique des inclusions nucléaires CAG, étudié en détail chez les souris transgéniques et en culture cellulaire, reste discuté : protecteur, par séquestration d'une protéine toxique [42], ou délétère, en piégeant dans le noyau des facteurs de transcription (pour revue, voir [43]). …”