C9orf72-mediated ALS and FTD: multiple pathways to disease

The discovery that repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has revolutionized our understanding of these diseases. Substantial headway has been made in characterizing C9orf72-mediated disease and unravelling its underlying aetiopathogenesis. Three main disease mechanisms have been proposed: loss of function of the C9orf72 protein and toxic gain of function from C9orf72 repeat RNA or from dipeptide repeat proteins produced by repeat-associated non-ATG translation. Several downstream processes across a range of cellular functions have also been implicated. In this article, we review the pathological and mechanistic features of C9orf72-associated FTD and ALS (collectively termed C9FTD/ALS), the model systems used to study these conditions, and the probable initiators of downstream disease mechanisms. We suggest that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-autonomous and non-cell-autonomous effects contributes to disease progression

Hormonal regulation of hippocampal dendritic morphology and synaptic plasticity

The peripheral functions of hormones such as leptin, insulin and estrogens are well documented. An important and rapidly expanding field is demonstrating that as well as their peripheral actions, these hormones play an important role in modulating synaptic function and structure within the CNS. The hippocampus is a major mediator of spatial learning and memory and is also an area highly susceptible to epileptic seizure. As such, the hippocampus has been extensively studied with particular regard to synaptic plasticity, a process thought to be necessary for learning and memory. Modulators of hippocampal function are therefore of particular interest, not only as potential modulators of learning and memory processes, but also with regard to CNS driven diseases such as epilepsy. Hormones traditionally thought of as only having peripheral roles are now increasingly being shown to have an important role in modulating synaptic plasticity and dendritic morphology. Here we review recent findings demonstrating that a number of hormones are capable of modulating both these phenomena

Preservation of motor neuron Ca2+ channel sensitivity to insulin-like growth factor-1 in brain motor cortex from senescent rat

Despite the multiple effects on mammals during development, the effectiveness of the insulin-like growth factor-1 (IGF-1) to sustain cell function and structure in the brain of senescent mammals is almost completely unknown. To address this issue, we investigated whether the effects of IGF-1 on specific targets are preserved at later stages of life. Voltage-gated Ca2+ channels (VGCC) are well-characterized targets of IGF-1. VGCC regulate membrane excitability and gene transcription along with other functions that have been found to be impaired in the brain of senescent rodents. As the voluntary control of movement has been reported to be altered in the elderly, we investigated the expression, function and responsiveness of high (HVA)- and low-voltage-activated (LVA) Ca2+ channels to IGF-1, using the whole-cell configuration of the patch-clamp and RT-PCR in the specific region of the rat motor cortex that controls hindlimb muscle movement. We detected the expression of α1A, α1B and α1E genes encoding the HVA Ca2+ channels P/Q, N and R, respectively, but not α1C, α1D, α1S encoding the L-type Ca2+ channel in this region of the brain cortex. IGF-1 enhanced Ca2+ channel currents through P/Q- and N-type channels but not significantly through the R-type or LVA channels. IGF-1 enhanced the amplitude but did not modify the voltage dependence of Ca2+ channel currents in young (2- to 4-week-old), young adult (7-month-old) and senescent (28- to 29-month-old) rats. These results support the concept that despite the reported decrease in circulating (liver) and local (central nervous system) production of IGF-1 with ageing, key neuronal targets such as the VGCC remain responsive to the growth factor throughout life