Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS

Unified theory of TSE neurodegeneration 2

Our findings evoke a new pathogenic model for neuroddegeneration in TSE. In prion diseases, functional interactions of PrP with its binding partner(s) have been suggested previously (Telling et al., 1995; Shmerling et al., 1998): a cis- and/or trans-interacting PrP activates an unknown binding partner competing with the dominant-negative mutant of PrP truncated at the amino terminus leading to ataxia and cerebellar lesions (Shmerling et al., 1998). We have now identified NCAM as binding partner for PrP that can cooperate with PrP in neurite outgrowth. It is likely that cooperation between these molecules also occurs in the adult. It is thus noteworthy that both NCAM and PrPC have been implicated in modification of synaptic activity (Collinge et al., 1994; Luthi et al., 1994; Cremer et al., 1994; Mallucci et al., 2002). Interestingly, defects in NCAM and PrP dependent regulation of synaptic activity may not only be due to developmental abnormalities, but are seen in mice conditionally ablated for NCAM and PrP expression at a juvenile state (Mallucci et al., 2002; Bukalo et al., 2004). Furthermore, mutations in PrP in both humans and mice lead to abnormal sleep patterns, resulting in fatal familial insomnia in humans (Gambetti et al., 2003). These finding are remarkable in view of PrP and NCAM signalling through fyn, which is also implicated in modifying synaptic functions (Grant et al., 1992; Kojima et al., 1997).

Finally, consequences of the trans- and cis-interactions between NCAM and PrP for transmissible and non-transmissible prion diseases, leading to infectious propagation of the mutation with its loss-of-function or gain-of-function consequences should be viewed in the context of PrP interacting heterophilically with other molecules, such as NCAM. Interestingly, the incubation period of the scrapie conformer of prion protein (PrPSc) is not altered in NCAM-/- mice compared to NCAM+/+ mice, suggesting that NCAM does not affect PrPSc formation (Schmitt-Ulms et al., 2001). Also, it has been excluded that neurodegeneration occurs because of PrP deficiency (Mallucci et al., 2002). It is thus conceivable that interactions between PrP and NCAM are altered by accumulation of PrPSc in the diseased nervous system. A reduced association between PrP and NCAM could also be caused by application of PrP antibodies that trigger rapid and extensive apoptosis in hippocampal and cerebellar neurons in vivo (Solforosi et al., 2004). Similarly, we found that application of PrP antibodies abrogates NCAM-induced neurite outgrowth. It is tempting to speculate that interference with NCAM-mediated signalling in the diseased brain may favour cell death and inhibit synaptic plasticity related neuritogenesis.

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