PMC:6610326 / 68997-74554
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/6610326","sourcedb":"PMC","sourceid":"6610326","source_url":"https://www.ncbi.nlm.nih.gov/pmc/6610326","text":"Neuroprotective and Neurotoxic Factor Expression in MN Subpopulations\nDifferential expression of pro-survival or toxic factors is also implicated in the specific vulnerability of MN subtypes. The IGFs are proteins with high homology to insulin that form part of the IGF “axis” that promotes cell proliferation and inhibits apoptosis. In the normal rat, IGF-I is highly expressed in oculomotor neurons, where it is protective against glutamate-induced toxicity (Hedlund et al., 2010; Allodi et al., 2016). This may be due to activation of the PI3K/Akt and p44/42 MAPK pathways, which both inhibit apoptosis (Siddle et al., 2001; Sakowski et al., 2009). In addition, its associated receptor, IGF-I receptor (IGF-IR), is also highly expressed in oculomotor neurons and on the extraocular muscle endplate (Allodi et al., 2016). IGF-IR is important for the survival of neurons following hypoxic/ischemic injury (Vincent and Feldman, 2002; Liu et al., 2011) by upregulation of neuronal cellular inhibitor of apoptosis-1 (cIAP-1) and X-linked inhibitor of apoptosis (XIAP) (Liu et al., 2011). Delivery of IGF-II using AAV9 to the muscle of mutant SOD1G93A mice extended life-span by 10%, prevented the loss of MNs and induced motor axon regeneration (Allodi et al., 2016). These findings indicate that differential expression of IGF-II and IGF-IR in oculomotor neurons might contribute to their relative resistance to degeneration in ALS/FTD.\nConversely, aberrant expression of axon repulsion factors near the NMJ may contribute to neurodegeneration in ALS. Sema3A and its receptor neuropilin 1 (Nrp1) are involved in axon guidance during neural development (Huber et al., 2005; Moret et al., 2007). Sema3A is specifically upregulated in terminal Schwann cells near NMJs of vulnerable FF muscle fibers in mutant SOD1G93A mice (De Winter et al., 2006). Nrp1 is upregulated in axon terminals of the NMJ in this model and administration of an antibody against the Sema3A-binding domain of Nrp1 delayed the decline of motor functions while prolonging the lifespan of SOD1G93A mice (Venkova et al., 2014). Furthermore, Sema3A is upregulated in the motor cortex of ALS patients (Körner et al., 2016; Birger et al., 2018), but not in the spinal cord. Sema3A induces death of sensory, sympathetic, retinal and cortical neurons (Shirvan et al., 2002; Ben-Zvi et al., 2008; Jiang et al., 2010; Wehner et al., 2016), but not spinal neurons (Molofsky et al., 2014; Birger et al., 2018). Similarly, Sema3A induces apoptosis of human cortical neurons but promotes survival of spinal MNs (Birger et al., 2018). Furthermore, loss of Sema3A-expressing astrocytes in the ventral spinal cord leads to selective degeneration of α-MNs, but not γ-MNs (Hochstim et al., 2008; Molofsky et al., 2014). These data indicate that whilst Sema3A and Nrp1 contribute to the loss of MNs in ALS, some neuronal subpopulations are more susceptible than others. There is also evidence that other axon guidance proteins are associated with the susceptibility of MNs in ALS. Increased expression of ephrin A1 has been demonstrated in the vulnerable spinal MNs of ALS patients (Jiang et al., 2005). EPHA4, which is a disease modifier in zebrafish, rodent models and human ALS, encodes an Eph receptor tyrosine kinase, which is involved in axonal repulsion during development and in synapse formation, plasticity and memory in adults (Van Hoecke et al., 2012). The more vulnerable MNs express higher levels of EPHA4, and neuromuscular re-innervation is inhibited by Epha4. In ALS patients, EPHA4 expression also inversely correlates with disease onset and survival (Van Hoecke et al., 2012).\nMatrix Metalloproteinase (MMP9) has been recently identified as another determinant of selective neuronal vulnerability in SOD1G93A mice (Kaplan et al., 2014). MMP-9 was strongly expressed by vulnerable FR spinal MNs, but not oculomotor, Onuf’s nuclei or S α-MNs, and it enhanced ER stress and mediated muscle denervation in this model (Kaplan et al., 2014). Delivery of MMP-9 into FF-MNs, but not in oculomotor neurons, accelerates denervation in SOD1G93A mice (Kaplan et al., 2014). Similarly, another study demonstrated that reduction of MMP-9 expression attenuated neuromuscular defects in rNLS8 mice expressing cytoplasmic hTDP43ΔNLS in neurons (Spiller et al., 2019). Edaravone, a free radical scavenger which inhibits MMP-9 expression, was recently approved for the treatment of ALS in Japan, South Korea, United States and Canada (Yoshino and Kimura, 2006; Ito et al., 2008; Yagi et al., 2009). Further molecular investigations into the differences and similarities between different motor units in ALS should yield additional insights into their vulnerability to neurodegeneration.\nPolymorphisms in specific genes have also been linked to MN vulnerability. In SALS patients, variants in the gene encoding UNC13A are associated with greater susceptibility to disease and shorter survival (Diekstra et al., 2012). UNC13A functions in vesicle maturation during exocytosis and it regulates the release of neurotransmitters, including glutamate. Mutations in EPHA4 are also associated with longer survival (Van Hoecke et al., 2012), implying that Epha4 modulates the vulnerability of MNs in ALS. Furthermore, repeat expansions in the gene encoding ataxin 2 (ATXN2), which cause spinocerebellar ataxia type 2 (SCA2), are also increased in ALS patients compared to healthy controls (Ross et al., 2011). This implies that ATXN2 repeat expansions are also related to MN vulnerability to neurodegeneration in 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