In “Attack of the Oligomers,” we review how protein oligomers
are the primary neurotoxic agents not just in Parkinson’s disease
but also in Alzheimer’s (where they were discovered first) and
other amyloid-related diseases. The oligomers wreak havoc
throughout the cell, disrupting membranes and throwing protein
and ion homeostasis out of balance. However, the most critical
damage in Parkinson’s disease seems to be to mitochondria.
Evidence for this is manifold, from studies of animal models and
neural cell cultures, from the MPTP (1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine) studies mentioned earlier, from the fact that
paraquat and rotenone, toxins that target mitochondria, are
linked to Parkinson’s disease, but most important, from genetics.
Two of the Mendelian mutations that lead to recessive familial
Parkinson’s disease occur in proteins, PINK1 and parkin, which
are involved in recycling damaged mitochondria, strongly
implicating a role for mitochondria in disease development.
Whereas alpha-synuclein oligomers deal the most damage, the
disease does not seem to spread without the amyloid form also
being present, because injecting just oligomers, without amyloid
fibrils, into transgenic mice overexpressing alpha-synuclein does
not trigger spreading pathology. Thus, alpha-synuclein oligomers
and amyloid fibrils appear to be partners in crime; both are
required for Parkinson’s disease. Finally, we examine the role of
disease-related alpha-synuclein mutants and posit that neurons
raise the expression of the non-mutated allele to compensate,
increasing the total level of alpha-synuclein, thus promoting
disease progression. CLICK TO REVIEW