Huntington's disease is caused by an abnormal polyglutamine expansion within the protein huntingtin and is characterized by microscopic inclusion bodies of aggregated huntingtin and by the death of selected types of neuron. Whether inclusion bodies are pathogenic, incidental or a beneficial coping response is controversial. To resolve this issue we have developed an automated microscope that returns to precisely the same neuron after arbitrary intervals, even after cells have been removed from the microscope stage. Here we show, by survival analysis, that neurons die in a time-independent fashion but one that is dependent on mutant huntingtin dose and polyglutamine expansion; many neurons die without forming an inclusion body. Rather, the amount of diffuse intracellular huntingtin predicts whether and when inclusion body formation or death will occur. Surprisingly, inclusion body formation predicts improved survival and leads to decreased levels of mutant huntingtin elsewhere in a neuron. Thus, inclusion body formation can function as a coping response to toxic mutant huntingtin.

/pdf/inclusion-body-formation-reduces-levels-of-mutant-huntingtin-41olhmmjql.pdf

Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death

Neuronal apoptosis sculpts the developing brain and has a potentially important role in neurodegenerative diseases. The principal molecular components of the apoptosis programme in neurons include Apaf-1 (apoptotic protease-activating factor 1) and proteins of the Bcl-2 and caspase families. Neurotrophins regulate neuronal apoptosis through the action of critical protein kinase cascades, such as the phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase pathways. Similar cell-death-signalling pathways might be activated in neurodegenerative diseases by abnormal protein structures, such as amyloid fibrils in Alzheimer's disease. Elucidation of the cell death machinery in neurons promises to provide multiple points of therapeutic intervention in neurodegenerative diseases.

/pdf/apoptosis-in-the-nervous-system-3rv035g8mp.pdf

Apoptosis in the nervous system

To elucidate the role of the synaptic protein alpha-synuclein in neurodegenerative disorders, transgenic mice expressing wild-type human alpha-synuclein were generated. Neuronal expression of human alpha-synuclein resulted in progressive accumulation of alpha-synuclein-and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus, and substantia nigra. Ultrastructural analysis revealed both electron-dense intranuclear deposits and cytoplasmic inclusions. These alterations were associated with loss of dopaminergic terminals in the basal ganglia and with motor impairments. These results suggest that accumulation of wild-type alpha-synuclein may play a causal role in Parkinson's disease and related conditions.

https://science.sciencemag.org/content/sci/287/5456/1265.full.pdf

Dopaminergic Loss and Inclusion Body Formation in α-Synuclein Mice: Implications for Neurodegenerative Disorders

Huntingtin Acts in the Nucleus to Induce Apoptosis but Death Does Not Correlate with the Formation of Intranuclear Inclusions

Oligomeric and Fibrillar Species of Amyloid-β Peptides Differentially Affect Neuronal Viability

https://www.cell.com/cell/pdf/S0092-8674(00)81781-X.pdf

Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice.

Spinocerebellar ataxia type 1 (SCA1) is one of several neurodegenerative disorders caused by an expansion of a polyglutamine tract. It is characterized by ataxia, progressive motor deterioration, and loss of cerebellar Purkinje cells. To understand the pathogenesis of SCA1, we examined the subcellular localization of wild-type human ataxin-1 (the protein encoded by the SCA1 gene) and mutant ataxin-1 in the Purkinje cells of transgenic mice. We found that ataxin-1 localizes to the nuclei of cerebellar Purkinje cells. Normal ataxin-1 localizes to several nuclear structures approximately 0.5 microm across, whereas the expanded ataxin-1 localizes to a single approximately 2-microm structure, before the onset of ataxia. Mutant ataxin-1 localizes to a single nuclear structure in affected neurons of SCA1 patients. Similarly, COS-1 cells transfected with wild-type or mutant ataxin-1 show a similar pattern of nuclear localization; with expanded ataxin-1 occurring in larger structures that are fewer in number than those of normal ataxin-1. Colocalization studies show that mutant ataxin-1 causes a specific redistribution of the nuclear matrix-associated domain containing promyelocytic leukaemia protein. Nuclear matrix preparations demonstrate that ataxin-1 associates with the nuclear matrix in Purkinje and COS cells. We therefore propose that a critical aspect of SCA1 pathogenesis involves the disruption of a nuclear matrix-associated domain.

Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures

This corrects the article DOI: 10.1038/40153

/pdf/erratum-ataxin-1-with-an-expanded-glutamine-tract-alters-42409pc39y.pdf

Ivan A. Klement

Papers

Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice.

Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures

Erratum: Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures (Nature (1997) 389 (971-974))

Pathogenesis of Polyglutamine-Induced Disease: A Model for SCA1