Hereditary spastic paraplegia (HSP) is a genetically heterogeneous disease caused by mutations in many genes, including those encoding spastin, strumpellin, or REEP1. Allison et al. show that similar lysosomal phenotypes are associated with mutations in different classes of HSP proteins and suggest that defective ER–endosome contacts and endosome tubule fission may be a common cause of axon degeneration in the disease.

The mechanisms underlying disease modifier gene effects are rarely understood. Newton et al. report that deletion of DPY30 reduces age at onset in hereditary spastic paraplegia caused by SPAST mutations. They demonstrate that both genes regulate cellular pathways that pathologically impact lysosome function, providing a mechanistic explanation for this interaction.

Mutants of neuroserpin are retained as polymers within the endoplasmic reticulum (ER) of neurones to cause the autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies or FENIB. The cellular consequences are unusual in that the ordered polymers activate the ER overload response (EOR) in the absence of the canonical unfolded protein response. We use both cell lines and Drosophila models to show that the G392E mutant of neuroserpin that forms polymers is degraded by UBE2j1 E2 ligase and Hrd1 E3 ligase while truncated neuroserpin, a protein that lacks 132 amino acids, is degraded by UBE2g2 (E2) and gp78 (E3) ligases. The degradation of G392E neuroserpin results from SREBP-dependent activation of the cholesterol biosynthetic pathway in cells that express polymers of neuroserpin (G392E). Inhibition of HMGCoA reductase, the limiting enzyme of the cholesterol biosynthetic pathway, reduced the ubiquitination of G392E neuroserpin in our cell lines and increased the retention of neuroserpin polymers in both HeLa cells and primary neurones. Our data reveal a reciprocal relationship between cholesterol biosynthesis and the clearance of mutant neuroserpin. This represents the first description of a link between sterol metabolism and modulation of the proteotoxicity mediated by the EOR.

The production, quality control, and degradation of proteins are a tightly controlled process necessary for cell health. In order to regulate this process, cells rely upon a network of molecular chaperone proteins that bind misfolded proteins and help them fold correctly. In addition, some molecular chaperones can target terminally misfolded proteins for degradation. Neurons are particularly dependent upon this “proteostasis” system, failures in which lead to neurodegenerative disease. In this review, we identify opportunities for modulating molecular chaperone activity with small molecules, which could lower the burden of misfolded protein within neurons, reducing cell death and ameliorating the effects of neurodegeneration. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

Recycling of cargos from early endosomes requires regulation of endosomal tubule formation and fission. This regulation is disrupted in cells depleted of the microtubule severing enzyme spastin, causing elongation of endosomal tubules and mis-trafficking of recycling endosomal cargos such as the transferrin receptor. Spastin is encoded by SPAST, mutations in which are the most frequent cause of autosomal dominant hereditary spastic paraplegia, a condition characterised by a progressive loss of lower limb function resulting from upper motor neuron axonopathy. Investigation of molecular factors involved in endosomal tubule regulation is hindered by the need for manual counting of endosomal tubules. We report here the development of an open source automated system for the quantification of endosomal tubules, using ImageJ and R. We validate the method in cells depleted of spastin and its binding partner IST1. The additional speed and reproducibility of this system compared with manual counting makes feasible screens of candidates to further understand the mechanisms of endosomal tubule formation and fission.