Using spastic paraplegia type 4 (SPG4, the most frequent HSP subtype) as an exemplar, we here present three rapid phenotypic assays for uncovering neuronal process pathologies in iPSC-derived glutamatergic cortical neurons.
The AAA+ ATPase spastin remodels microtubule arrays through severing and its mutation is the most common cause of hereditary spastic paraplegias (HSP).
Expression of the mutant spastin was documented from fetus to adult, but gait defects reminiscent of HSP (not observed in spastin knockout mice) were adult onset, as is typical of human patients.
Missense mutations of the SPAST gene are frequently detected in patients with hereditary spastic paraplegias (HSPs) and represent the main reason of loss of SPAST function; however, the pathogenicity of mutant SPAST is heterogeneous.
Experiments presented here using isolated squid axoplasm reveal inhibition of FAT as a common toxic effect elicited by spastin proteins with different HSP mutations, independent of microtubule-binding or severing activity.
Here, utilizing null SPAST homologues in C. elegans, Drosophila and zebrafish, we tested FDA-approved compounds known to modulate ER stress in order to ameliorate locomotor phenotypes associated with HSP.
A molecular diagnosis was obtained in 82.1 % of the cases (52 cases with mutations in SPAST/SPG4, two in SPG7, and one in SPG11).The prevalence of HSP among Sardinians is high compared with other Western European populations.
We investigated the white matter features of spastic gait (SPG)11- and SPG4-linked HSP, using diffusion tensor imaging performed with a 3-Tesla (3T) scanner.
We describe a large, AD-HSP Sardinian family where 5 out of several living members harbored a novel deletion affecting also the 5'UTR of SPAST and resulting in reduced expression of DPY30, the gene located upstream SPAST in a head-to-head manner.