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Defects of mitochondrial polymerase gamma (POLG) underlie neurological diseases ranging from myopathies to parkinsonism and infantile Alpers syndrome. The most severe manifestations have been associated with mutations of the 'spacer' region of POLG, the function of which has remained unstudied in humans. We identified a family, segregating three POLG amino acid variants, A467T, R627Q and Q1236H. The first two affect the spacer region and the third is a polymorphism, allelic with R627Q. Three grades of disease severity appeared to correlate with the genotypes. The patient with the most severe outcome, cerebellar ataxia syndrome, had all three variants, those with R627Q and Q1236H had juvenile-onset ptosis and gait disturbance and those with a single A467T allele had late-onset ptosis. To evaluate the molecular pathogenesis of these spacer defects, we expressed and purified the mutant proteins and studied their catalytic properties in vitro. The A467T substitution resulted in clearly decreased activity, DNA binding and processivity of the polymerase. Our biochemical data, the dominant manifestation of A467T and its previously reported high frequency in the Belgian population (0.6%), emphasize the role of this mutation as a common cause of neurological disease. Further, biochemical evidence that a polymorphic variant may modify the function of a mutant POLG, if occurring in the same polypeptide, is shown here. Finally, and surprisingly, other pathogenic spacer mutants showed DNA-binding affinities and processivities similar to or higher than the controls, suggesting that the disease-causing mechanisms of spacer mutations extend beyond the basic catalytic functions of POLG.

Creutzfeldt-Jakob disease (CJD) and Alzheimer's disease (AD) share clinical, neuropathological, and pathogenetic features. To investigate eventual mutual influences, we screened prominently affected neocortex from 110 neuropathologically proven CJD patients for Alzheimer-type pathology with anti-beta/A4, Bielschowsky and anti-tau (immuno)stains. The neuropathological classification of Alzheimer-type pathology was made according to the CERAD criteria. Results were controlled by comparison with Alzheimer-type changes in sections from the same cortical areas in 110 sex- and age-matched non-demented control patients. For comparison, the control patients were also classified according to the CERAD neuropathology criteria as if they had been demented. Alzheimer-type tissue changes as in definite and probable CERAD AD occur in 10.9% of the CJD patients and 19.1% of control patients (P=0.11). The median age of CJD and control patients with CERAD AD is 72 and 68 years, respectively, which differs significantly from the median ages of 64 and 63 years, respectively, in the non-AD/CJD and non-AD control patients. Since CERAD criteria include "presence of other neuropathological lesions likely to cause dementia", an AD diagnosis in CJD patients (all of whom are demented) is solely based on densities of neuritic plaques. Similar Alzheimer-type changes in even higher frequency, however, are also present in elderly non-demented controls. Thus, the coexistence of Alzheimer-type pathology in CJD most likely represents an age-related change. Deposits of prion protein (PrP) frequently accumulate at the periphery of beta/A4 plaques. The presence of beta/A4 amyloid in the brain may influence PrP morphogenesis.

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