Although Huntington and Alzheimer diseases have different underlying causes, the similarities in the neuronal Ca2+ increases observed in the Romero et al. study with the Ca2+ signaling dysregulations observed in AD point to a growing consensus that Ca2+ signaling alterations can be an early pathogenic factor in neurodegenerative disease. In this study, the authors expressed full-length expanded htt protein with a 128-glutamine repeat in Drosophila neurons to replicate the HD condition. Expression of this expanded protein did not result in nuclear or axonal abnormalities, but did generate Ca2+-linked alterations in synaptic transmission via two mechanisms. First, expanded htt led to an increase in synaptic transmission at the neuromuscular junction due to increased vesicle release. This may be related to Ca2+, since it is a fundamental component of neurotransmitter release, and increased Ca2+ in the nerve terminal will increase probability of release and reduce ”failure” rate. Second, resting Ca2+ levels in nerve terminals were twice that of controls, and likely linked to...  Read more

Although Huntington and Alzheimer diseases have different underlying causes, the similarities in the neuronal Ca2+ increases observed in the Romero et al. study with the Ca2+ signaling dysregulations observed in AD point to a growing consensus that Ca2+ signaling alterations can be an early pathogenic factor in neurodegenerative disease. In this study, the authors expressed full-length expanded htt protein with a 128-glutamine repeat in Drosophila neurons to replicate the HD condition. Expression of this expanded protein did not result in nuclear or axonal abnormalities, but did generate Ca2+-linked alterations in synaptic transmission via two mechanisms. First, expanded htt led to an increase in synaptic transmission at the neuromuscular junction due to increased vesicle release. This may be related to Ca2+, since it is a fundamental component of neurotransmitter release, and increased Ca2+ in the nerve terminal will increase probability of release and reduce ”failure” rate. Second, resting Ca2+ levels in nerve terminals were twice that of controls, and likely linked to expanded htt-induced changes in presynaptic voltage-gated Ca2+ channels. These HD synaptic alterations are reversed by reducing Ca2+ in the nerve terminals and reducing expression of the presynaptic voltage-gated Ca2+ channels. The functional implications of increased transmitter release could include postsynaptic excitotoxicity, receptor downregulation, impaired downstream signaling, and motor/sensory/learning deficits. Long-term effects could contribute to loss of synaptic efficacy and cell death, characteristic of HD and AD.

These specific disruptions in presynaptic terminals are an important addition to the existing list of Ca2+ alterations associated with HD (and AD in some cases). Increased NMDA Ca2+ flux in neurons, increased resting Ca2+ levels in CA1 hippocampal neurons, increased ER Ca2+ release due to sensitized IP3R, and altered mitochondrial Ca2+ buffering are cited as well. Notably, increased ER Ca2+ release is observed with PS mutations in FAD, while in sporadic AD, Aβ and tau pathology can increase Ca2+ levels and vice versa (see Stutzmann, 2007 for review) . And, in Parkinson disease, α-synuclein aggregation is linked to altered Ca2+ influx (Danzer et al., 2007). In these progressive and adult-onset neurodegenerative disorders, early Ca2+ alterations are observed in many stages of the disease process and display localized subcellular and functional specificity. These Ca2+-driven alterations likely impair neuronal function and contribute to the later global pathology that defines the specific neurodegenerative disease. Likewise, this study offers additional support for Ca2+-based therapeutic strategies to treat early stages of neurodegenerative disease.

View all comments by Grace (Beth) Stutzmann