Parkinson's disease and amyotrophic lateral sclerosis

Parkinson's Disease (PD) and Amyotrophic Lateral Sclerosis (ALS) are common neurodegenerative disorders in the aging population. The primary pathological characteristics of PD are the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and reductions in their termini within the dorsal striatum (see Przedborski, Chapter 26). These lead to profound and irreversible striatal dopamine loss. Cell modeling data indicate that 100-200 SNpc neurons degenerate per day during PD (Orr et al., 2002). ALS, also known as Lou Gehrig's disease, is characterized by gradual degeneration of spinal cord motor neurons eventually leading to progressive weakness, paralysis of muscle, and death (see Simpson et al., Chapter 27). The mechanisms for neurodegeneration in both disorders relate, in part, to the abnormal accumulation, oligomer formation and misfolding of a-synuclein for PD and superoxide dismutase 1 (SOD1) for ALS. These protein aggregates form at synapses and axons leading to signaling abnormalities and neuronal dysfunction. Neuroinflammatory responses, mitochondrial function, glutamate transport toxicity, and free radicals formulation are linked as a consequence of protein toxicities and lead to neuronal destruction in both disorders. It is hypothesized, all together, that changes in the balance between factors promoting aggregation, clearance and synthesis of a-synuclein and SOD1 is a central component of disease pathogenesis. Microglial activation and alterations in lysosomal function are linked to oligomer accumulation. These can accumulate in the membrane and can be recognized by antibodies that promote their clearance (Masliah et al., 2005). Antibodies can lead to decreased accumulation of aggregated a-synuclein in neuronal cell bodies and synapses associated with reduced neurodegeneration. Antibodies can also recognize abnormal a-synuclein associated with the neuronal membrane and promote their degradation through lysosomal-autophagy pathways. Thus, vaccination is effective in reducing the neuronal accumulation of a-synuclein aggregates and further development of this approach might have a potential role in the treatment of PD (Miller and Messer, 2005). Such an anti-amyloidogenic property might also provide a novel strategy for the treatment of other neurodegenerative disorders. Antibodies specific for peptides or conformations of misfolding neurodegenerative disease proteins can be engineered for affinity and stability; and then delivered intracellularly as intrabodies. For SOD1-linked familial ALS, aberrant oligomerization of SOD1 mutant proteins has been implicated. Formation of soluble oligomers suggests a general, unifying picture of SOD1 aggregation linked to neuronal destruction. Thus, vaccination with a-synuclein or SOD1 has been proposed for treatment of disease. In the case of ALS, vaccination with recombinant SOD1 or passive immunization with antibodies against SOD1 species has been tested with success in mouse models of ALS. These parallel similar successes in rodent models of PD. This therapeutic approach is based on reduction of toxic mutant proteins. However, caution is noted in developing such approaches. Work from our own laboratory has shown the importance of the cell-mediated adaptive immune system in neuroprotective treatment strategies for PD and ALS. In particular, T cells have beneficial and harmful affects on neurodegenerative processes. Immunoregulatory treatments [e.g., glatiramer acetate (GA), vasoactive intestinal peptide (VIP), granulocyte macrophage-colony stimulating factor (GM-CSF), and 1,25-dihydroxyvitamin D3] that modulate T cell responses can play an important role in future immunotherapies. In this chapter we review the roles of the innate and adaptive immune system in the pathogenesis of PD and ALS and the recently developed means to harness both for therapeutic benefit (Figure 44.1).