Table 2.

Potential pathways for pathogenesis of Huntington’s disease (HD)

Neuronal aggregates

Neuronal intracytoplasmic and intranuclear inclusions containing mutant huntingtin, truncated N-terminal mutant and wild-type fragment, and chaperones and components of the proteolytic pathway are characteristic of HD neuropathology

Accumulation of mutant protein aggregates may be a result of impairment of the ubiquitin–proteosome pathway

Autophagic mechanisms are implicated in the clearance of protein aggregates

Transcriptional dysregulation

Aberrant nuclear localization of mutant toxic huntingtin fragments and their association with transcription factors

Dysregulation related to entrapment of transcriptional factors in protein aggregates

Excitotoxicity

Excitotoxic neuron death in HD could result from a combination of increased glutamate and glutamate agonist release from cortical afferents

Mitochondrial dysfunction and altered energy metabolism

Selective inhibitors of complex II of the mitochondrial electron transport chain, 3- nitropropionic acid, and malonate, cause selective striatal neuronal loss similar to that seen in patients with HD

Multitude of bioenergetic defects have been reported in patients with HD

Changes in axonal transport and synaptic dysfunction

Normal huntingtin plays a role in axonal trafficking

Disruption of axonal transport contributes to pathologic process in HD