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Abstract
Nogo/reticulon (RTN)-4 has been strongly implicated as a disease marker for the motor neuron disease amyotrophic lateral sclerosis (ALS). Nogo isoforms, including Nogo-A, are ectopically expressed in the skeletal muscle of ALS mouse models and patients and their levels correlate with the disease severity. The notion of a direct involvement of Nogo-A in ALS aetiology is supported by the findings that Nogo-A deletion in mice reduces muscle denervation and prolongs survival, whereas overexpression of Nogo-A destabilizes motor nerve terminals and promotes denervation. Another intriguing, and somewhat paradoxical, recent finding revealed that binding of the Nogo-66 receptor (NgR) by either agonistic or antagonistic Nogo-66-derived peptides protects against p75 neurotrophin receptor (p75NTR)-dependent motor neuron death. Ligand binding by NgR could result in subsequent engagement of p75NTR, and this association could preclude pro-apoptotic signalling by the latter. Understanding the intricate interplay among Nogo isoforms, NgR and p75NTR in ALS disease progression may provide important, therapeutically exploitable information.
Highlights
The adult central nervous system (CNS) myelin-associated Nogo [1,2,3] has been intensively investigated pertaining to its role in inhibiting CNS neuronal regeneration [4,5,6]
TAJ/TROY, an orphan TNF receptor family member broadly expressed during the development and in adult neurons, could serve as an alternative Nogo66 receptor (NgR) co-receptor in place of p75 neurotrophin receptor (p75NTR) [20, 21]
Nogo-A expression correlated, in particular, with the atrophy of the slow-twitch type 1 fibres, and almost all Nogo-A-positive fibres of this type appeared atrophic. These findings suggest that Nogo-A may be a useful marker to monitor amyotrophic lateral sclerosis (ALS) disease progression
Summary
The adult central nervous system (CNS) myelin-associated Nogo [1,2,3] has been intensively investigated pertaining to its role in inhibiting CNS neuronal regeneration [4,5,6]. TAJ/TROY, an orphan TNF receptor family member broadly expressed during the development and in adult neurons, could serve as an alternative NgR co-receptor in place of p75NTR [20, 21] Another membrane-spanning protein, LINGO-1 [22], may be necessary for the formation of a fully functional receptor complex that could transduce an inhibitory signal associated with Nogo-66–NgR binding. The exact role of Nogo and its signalling in ALS pathophysiology is not yet clearly defined, but the muscle Nogo-A levels correlate with disease severity [52] and appear to be, at least, partly responsible for muscle denervation [53, 54] It was found out very recently that NgR activation by Nogo66-derived peptides appeared to confer a survival advantage to the motor neurons [55]. We consider the neuropathological roles of Nogo and NgR in ALS in the light of these new findings
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