DISTORTION OF NEURONAL GEOMETRY AND FORMATION OF ABERRANT SYNAPSES IN NEURONAL STORAGE DISEASE

Golgi and EM studies of [human] cortical neurons in several lysosomal storage diseases were carried out to elucidate structural features of the large neural processes (meganeurites) that develop as storage sites for accumulated undigestible substrates. Meganeurites occurred preferentially in pyramidal neurons wherein they developed between the base of the perikaryon and the initial portion of the axon. They frequently gave rise to secondary neurites which bore filopodium-like processes. Meganeurites might possess spines some of which were contacted by presynaptic processes containing synaptic vesicles. The extent of meganeurite development was related to the onset, severity and clinical course of neuronal storage disease. Extensive development of bizarre and pleomorphic meganeurites occurs in classical Tay-Sachs disease (infantile GM2-gangliosidosis, B variant), whereas a smaller proportion of neurons exhibited meganeurites in juvenile GM2-gangliosidosis and Hurler''s disease. Meganeurites with spines and spine synapses were prominent in GM2-gangliosidosis, AB variant. Meganeurites and meganeurite synapses may contribute to the onset and progression of neuronal dysfunction in storage diseases by altering electrical properties of the neuron and modifying integrative operations of somadendritic synaptic inputs.