Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease thought to employ cell non-autonomous mechanisms where neuronal injury engages immune responses to influence disease progression. Here we show that the expression of mutant proteins causative for ALS in Caenorhabditis elegans motor neurons induces an innate immune response via TIR-1/Sarm1. Loss of function mutations in tir-1, associated downstream kinases, and the transcription factor atf-7 all suppress motor neuron degeneration. The neurosecretory proteins UNC-13 and UNC-31 are required for induction of the immune response as well as the degeneration of motor neurons. The human orthologue of UNC-13, UNC13A, has been identified as a genetic modifier of survival in ALS, and we provide functional evidence of UNC-13/UNC13A in regulating motor neuron degeneration. We propose that the innate immune system reacts to the presence of mutant proteins as a contagion, recruiting a pathogen resistance response that is ultimately harmful and drives progressive neurodegeneration.

Amyotrophic lateral sclerosis (ALS) is] i as a driver of TDP-43-mediated neuronal toxicity. Furthermore, we discovered that neuronal degeneration is independent of the executioner caspase CED-3, but instead requires the activity of the Ca 2ϩ -regulated calpain protease TRA-3, and the aspartyl protease ASP-4. Finally, chemically blocking protease activity protected against mutant TDP-43 A315T -associated neuronal toxicity. This work both underscores the potential of the C. elegans system to identify key targets for therapeutic intervention and suggests that a focused effort to regulate ER Ca 2ϩ release and necrosis-like degeneration consequent to neuronal injury may be of clinical importance.

Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous disease characterized by spasticity and weakness of the lower limbs with or without additional neurological symptoms. Although more than 70 genes and genetic loci have been implicated in HSP, many families remain genetically undiagnosed, suggesting that other genetic causes of HSP are still to be identified. HSP can be inherited in an autosomal-dominant, autosomal-recessive, or X-linked manner. In the current study, we performed whole-exome sequencing to analyze a total of nine affected individuals in three families with autosomal-recessive HSP. Rare homozygous and compound-heterozygous nonsense, missense, frameshift, and splice-site mutations in CAPN1 were identified in all affected individuals, and sequencing in additional family members confirmed the segregation of these mutations with the disease (spastic paraplegia 76 [SPG76]). CAPN1 encodes calpain 1, a protease that is widely present in the CNS. Calpain 1 is involved in synaptic plasticity, synaptic restructuring, and axon maturation and maintenance. Three models of calpain 1 deficiency were further studied. In Caenorhabditis elegans, loss of calpain 1 function resulted in neuronal and axonal dysfunction and degeneration. Similarly, loss-of-function of the Drosophila melanogaster ortholog calpain B caused locomotor defects and axonal anomalies. Knockdown of calpain 1a, a CAPN1 ortholog in Danio rerio, resulted in abnormal branchiomotor neuron migration and disorganized acetylated-tubulin axonal networks in the brain. The identification of mutations in CAPN1 in HSP expands our understanding of the disease causes and potential mechanisms.

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