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Calpain 1 in neurodegeneration: a therapeutic target?
Correspondence
Calpain 1 in neurodegeneration: a therapeutic target? We1 and others2 have recently reported that biallelic mutations in CAPN1 (the gene encoding calpain 1, a calciumdependent protease) cause autosomal recessive hereditary spastic paraplegia, spastic ataxia, or both. In the studies, 15 affected individuals from seven families of various origins (North American, Moroccan, Bangladeshi, Italian, Tunisian, French and Spanish), were identified as carriers of biallelic CAPN1 mutations. They typically presented with spastic paraplegia, ataxia, and dysarthria as common features, with age at onset ranging from late teens to late thirties. The mutations identified, mostly leading to early termination of the protein or potentially affecting its structure and function, suggest that loss of function of calpain 1 is responsible for hereditary spastic paraplegia and spastic ataxia in these patients. Further supporting this finding are results from the four knockdown or knockout models (in worms, flies, zebrafish, and mice), in which absence of calpain 1 orthologues led to neurodegeneration and motor impairment.1,2 Taken together, these results suggest that calpain 1 can have a neuroprotective role and that its dysfunction might lead to neurological symptoms. However, data from previous studies have suggested that inhibition of calpains, including calpain 1, might be neuroprotective in traumatic brain injury and Alzheimer’s disease in both animal models and human beings. Overactivation of calpains might contribute to the pathogenesis of these disorders, and specific calpain 1 inhibitors are being designed and tested as potential treatments in preclinical settings. 3 Furthermore, some calpain inhibitors are being tested in clinical trials (eg, ClinicalTrials. gov, NCT02220738). This therapeutic 1118
approach is based on the notion that inhibition of calpain 1 might stop the progression of neurodegeneration.1,2 Can calpain 1 be neuroprotective at its baseline expression levels and neurotoxic when overactivated? If so, in cases of overexpression or overactivation of calpain 1, its inhibition, at least to a certain degree, could be useful. However, it cannot be ruled out that the recorded over-activation of calpain 1 in Alzheimer’s disease and traumatic brain injury is a response seemingly aimed to control the damage rather than the cause of the cellular damage. Although findings of a recent study showed that calpain 1 is upregulated in Alzheimer’s brains at Braak stages III and IV, preceding the phosphorylation of tau, it was not upregulated in stage II brains.4 This finding suggests that the upregulation of calpain 1 could be downstream to cellular damage and the result of activation of a neuroprotective mechanism, rather than part of the pathogenic mechanism. Although calpains have been studied for decades, there are still gaps in understanding their function in human beings. Recently, based on accumulating data from various models, researchers hypothesised that calpain 1 and calpain 2 have opposing roles in the brain, including in synaptic plasticity and neuronal survival.5 The activation of calpain 1—as opposed to to activation of calpain 2, which is neuro-damaging—might promote neuroprotection and induce a signalling cascade resulting in changes to synaptic structure and long-term potentiation.5 More studies, preferably in human cells such as in neurons derived from induced pluripotent stem cells, are needed to establish whether or not specific calpain 1 inhibition could be a good strategy for the treatment of Alzheimer’s disease or traumatic brain injury. ZG-O reports personal fees and travel cost refund from Sanofi/Genzyme, outside the submitted work. GAR declares no competing interests.
*Ziv Gan-Or, Guy A Rouleau [email protected] Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, Department of Human Genetics, McGill University, Montreal, Quebec, H3A 2B4, Canada 1
2
3
4
5
Gan-Or Z, Bouslam N, Birouk N, et al. Mutations in CAPN1 cause autosomal-recessive hereditary spastic paraplegia. Am J Hum Genet 2016; 98: 1038–46. Wang Y, Hersheson J, Lopez D, et al. Defects in the CAPN1 gene result in alterations in cerebellar development and cerebellar ataxia in mice and humans. Cell Rep 2016; 16: 79–91. Fa M, Zhang H, Staniszewski A, et al. Novel selective calpain 1 inhibitors as potential therapeutics in Alzheimer’s disease. J Alzheimers Dis 2015; 49: 707–21. Kurbatskaya K, Phillips EC, Croft CL, et al. Upregulation of calpain activity precedes tau phosphorylation and loss of synaptic proteins in Alzheimer’s disease brain. Acta Neuropathol Commun 2016; 4: 34. Baudry M, Bi X. Calpain-1 and Calpain-2: The yin and yang of synaptic plasticity and neurodegeneration. Trends Neurosci 2016; 39: 235–45.
The sharp drop in the number of faculty positions is compromising the future of neuroscience As young European neuroscientists, we want to bring attention to the dramatic absence of professional long-term opportunities that researchers are facing mostly, although not exclusively, in the south of Europe. In the past few years, young scientists from several European countries have been forced to move to other countries, or to quit research altogether, because the chances for them to secure a permanent position in academia are very low. While European institutions are regularly funding the best research projects in Europe, some countries have started to neglect their responsibility in hiring new researchers. The funding for research projects in the absence of new permanent positions is resulting in a perfect storm, which is especially worrisome for the domain
www.thelancet.com/neurology Vol 15 October 2016
Calpain 1 in neurodegeneration: a therapeutic target? We1 and others2 have recently reported that biallelic mutations in CAPN1 (the gene encoding calpain 1, a calciumdependent protease) cause autosomal recessive hereditary spastic paraplegia, spastic ataxia, or both. In the studies, 15 affected individuals from seven families of various origins (North American, Moroccan, Bangladeshi, Italian, Tunisian, French and Spanish), were identified as carriers of biallelic CAPN1 mutations. They typically presented with spastic paraplegia, ataxia, and dysarthria as common features, with age at onset ranging from late teens to late thirties. The mutations identified, mostly leading to early termination of the protein or potentially affecting its structure and function, suggest that loss of function of calpain 1 is responsible for hereditary spastic paraplegia and spastic ataxia in these patients. Further supporting this finding are results from the four knockdown or knockout models (in worms, flies, zebrafish, and mice), in which absence of calpain 1 orthologues led to neurodegeneration and motor impairment.1,2 Taken together, these results suggest that calpain 1 can have a neuroprotective role and that its dysfunction might lead to neurological symptoms. However, data from previous studies have suggested that inhibition of calpains, including calpain 1, might be neuroprotective in traumatic brain injury and Alzheimer’s disease in both animal models and human beings. Overactivation of calpains might contribute to the pathogenesis of these disorders, and specific calpain 1 inhibitors are being designed and tested as potential treatments in preclinical settings. 3 Furthermore, some calpain inhibitors are being tested in clinical trials (eg, ClinicalTrials. gov, NCT02220738). This therapeutic 1118
approach is based on the notion that inhibition of calpain 1 might stop the progression of neurodegeneration.1,2 Can calpain 1 be neuroprotective at its baseline expression levels and neurotoxic when overactivated? If so, in cases of overexpression or overactivation of calpain 1, its inhibition, at least to a certain degree, could be useful. However, it cannot be ruled out that the recorded over-activation of calpain 1 in Alzheimer’s disease and traumatic brain injury is a response seemingly aimed to control the damage rather than the cause of the cellular damage. Although findings of a recent study showed that calpain 1 is upregulated in Alzheimer’s brains at Braak stages III and IV, preceding the phosphorylation of tau, it was not upregulated in stage II brains.4 This finding suggests that the upregulation of calpain 1 could be downstream to cellular damage and the result of activation of a neuroprotective mechanism, rather than part of the pathogenic mechanism. Although calpains have been studied for decades, there are still gaps in understanding their function in human beings. Recently, based on accumulating data from various models, researchers hypothesised that calpain 1 and calpain 2 have opposing roles in the brain, including in synaptic plasticity and neuronal survival.5 The activation of calpain 1—as opposed to to activation of calpain 2, which is neuro-damaging—might promote neuroprotection and induce a signalling cascade resulting in changes to synaptic structure and long-term potentiation.5 More studies, preferably in human cells such as in neurons derived from induced pluripotent stem cells, are needed to establish whether or not specific calpain 1 inhibition could be a good strategy for the treatment of Alzheimer’s disease or traumatic brain injury. ZG-O reports personal fees and travel cost refund from Sanofi/Genzyme, outside the submitted work. GAR declares no competing interests.
*Ziv Gan-Or, Guy A Rouleau [email protected] Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, Department of Human Genetics, McGill University, Montreal, Quebec, H3A 2B4, Canada 1
2
3
4
5
Gan-Or Z, Bouslam N, Birouk N, et al. Mutations in CAPN1 cause autosomal-recessive hereditary spastic paraplegia. Am J Hum Genet 2016; 98: 1038–46. Wang Y, Hersheson J, Lopez D, et al. Defects in the CAPN1 gene result in alterations in cerebellar development and cerebellar ataxia in mice and humans. Cell Rep 2016; 16: 79–91. Fa M, Zhang H, Staniszewski A, et al. Novel selective calpain 1 inhibitors as potential therapeutics in Alzheimer’s disease. J Alzheimers Dis 2015; 49: 707–21. Kurbatskaya K, Phillips EC, Croft CL, et al. Upregulation of calpain activity precedes tau phosphorylation and loss of synaptic proteins in Alzheimer’s disease brain. Acta Neuropathol Commun 2016; 4: 34. Baudry M, Bi X. Calpain-1 and Calpain-2: The yin and yang of synaptic plasticity and neurodegeneration. Trends Neurosci 2016; 39: 235–45.
The sharp drop in the number of faculty positions is compromising the future of neuroscience As young European neuroscientists, we want to bring attention to the dramatic absence of professional long-term opportunities that researchers are facing mostly, although not exclusively, in the south of Europe. In the past few years, young scientists from several European countries have been forced to move to other countries, or to quit research altogether, because the chances for them to secure a permanent position in academia are very low. While European institutions are regularly funding the best research projects in Europe, some countries have started to neglect their responsibility in hiring new researchers. The funding for research projects in the absence of new permanent positions is resulting in a perfect storm, which is especially worrisome for the domain
www.thelancet.com/neurology Vol 15 October 2016