Survival in sporadic ALS linked to autophagy protein p62
Patients with longer survival had fewer p62 aggregates in spinal cord
Increased accumulation of p62, a protein involved in a cellular recycling process called autophagy, in the spinal cord is associated with worse survival outcomes in people with sporadic amyotrophic lateral sclerosis (ALS), a study revealed.
Autophagy is the cellular process responsible for breaking down proteins and other complex molecules that are abnormal or no longer needed. The buildup of p62 clumps generally indicates that this process is no longer working as it should, as the toxic protein aggregates contributing to ALS are not cleared properly.
“These findings implicate the autophagy pathway in ALS survival and provide support for further study of p62 as a potential prognostic biomarker in ALS,” researchers wrote.
The study, “Survival in sporadic ALS is associated with lower p62 burden in the spinal cord,” was published in the Journal of Neuropathology & Experimental Neurology. The work was funded by Australia’s FightMND.
In ALS, the loss of the specialized nerve cells that control voluntary movement, called motor neurons, results in symptoms such as muscle weakness and wasting, and an inability to control movement.
Both upper motor neurons, which connect the brain to the spinal cord, and lower motor neurons, extending from the spinal cord to muscles, are affected in people with the disease.
Formation of toxic clumps of TDP-43 protein occurs in almost all ALS patients
A hallmark of ALS, occurring in about 97% of patients, is the formation of toxic clumps of the TDP-43 protein, which contribute to motor neuron loss. The p62 protein, a marker for autophagy, is often found within these TDP-43 aggregates.
In this report, researchers at the University of Sydney investigated p62 aggregates in the motor neurons of 31 sporadic ALS patients to assess p62’s association with TDP-43 accumulation, neuron loss, and survival.
All participants had upper and lower motor neuron degeneration accompanied by TDP-43 protein clumps. A group of 15 patients had short disease duration, defined as less than two years (short survival), while 16 patients had a longer disease duration of 4-7 years (longer survival). There were no differences in age at death, site of onset, sex, or ALS stage between the two groups.
Tissue analysis of donated samples found the density of motor neurons in the spinal cord was significantly lower in patients who lived longer compared with those in the short-disease duration group.
No significant differences in neuron density were observed in the motor cortex, a part of the brain that generates signals to direct body movements, and the hypoglossal nucleus, a prominent cluster of large motor neurons that supply the tongue muscles.
Aggregates of p62 were detected in lower motor neurons, which had three types of structures: thread-like, dense and round, and dot-like. By contrast, p62 aggregates were not seen in upper motor neurons.
A significantly greater density of p62 aggregates was found in the spinal cord of the short-disease duration cases compared with longer duration cases, driven by mainly thread-like aggregates.
“Because the accumulation of p62 is considered an indicator of autophagy inhibition, the present findings of significantly more p62 aggregates in the spinal cord of patients with a shorter disease duration implicates deficits in [autophagy] pathways in ALS survival,” the researchers wrote.
Motor neurons with TDP-43 aggregates were significantly more common in the spinal cord and hypoglossal nucleus of the short compared with the extended survival group. Thread-like aggregates also were more prominent in the spinal cord of those with shorter survival. No significant difference was found in upper motor neurons.
Statistical analysis found a significant correlation between p62 and TDP-43 aggregates, and increasing p62 and TDP-43 aggregates were associated with increasing numbers of spinal cord motor neurons.
ALS patients with longer survival had significantly fewer p62 and TDP-43 aggregates and lower motor neuron density in the spinal cord.
“The present study demonstrates significantly more p62 aggregates in the spinal cord of patients with shorter ALS survival,” the team concluded. “Future longitudinal [over time] studies will be able to determine the viability of in vivo [in living organisms] measures of p62 expression in identifying patients with poorer prognosis at presentation.”