Alteration of the Clinical Progression of Motor Neuron Disease by addressing Epigenetic Insult, Cellular Debris, Unfolded Proteins and Ceramides with Bioactive Lipids, Phospholipids and Chaperones

Objective: Alteration of the clinical progression of motor neuron disease by identification and normalization of aberrant membrane leaflets, DNA adducts and clearance of cellular debris following epigenetic insult by utilizing chaperones, lipid mediators and phospholipids to optimize cellular function in motor neuron disorders.

Background: Genetic, epigenetic and neurological disorders are characterized by an accumulation of very-long-chain fatty acids, revealing cell membrane derangement per impaired peroxisomal respiration and ER stress, interrupting membrane integrity and neurometabolic function. Both nuclear and mitochondrial DNA adducts, that compromise gene expression, occur following epigenetic insult, perhaps explaining the intensely aggressive course of disease in subjects in metabolic distress as well as wide variations in the course of the disease. Epigenetic insult disrupts organelle interplay, reflected in both aberrant lipids (ceramides/lipid rafts, VLCFAs, sphingomyelin, oxidized lipids and cholesterol, distorted phospholipids formation) and proteins (aggregated, misfolded and unfolded) throughout the cellular components (ER, mitochondrion, peroxisome, nuclear envelope, Golgi).


Methods:   Examination of DNA adducts, cardiolipin stability,  mitochondrial/peroxisomal respiration status, analysis of membrane phospholipids and red cell lipids at Kennedy Krieger Peroxisomal Diseases Laboratory to examine the extent of  epigenetic insult reflected in signature aberrant fatty acids reflective of disturbed organelle, membrane and cellular function.  We apply exogenous phospholipid therapy both orally and intravenously to clear DNA adducts that arise from epigenetic antecedents, thereby optimizing organelle function. Therapeutic modalities include targeted bioactive lipids, phospholipids and chaperones.


Results: Our phospholipid, pro-resolving protocol has yielded marked clinical improvement in subjects following a six-month phospholipid regimen, with normalization of red cell lipid status.

Conclusion: Over a 20 year history of clinical application we have found that clearance of cellular debris and phospholipid supplementation to address membrane stabilization has resulted in improved cellular function in our subjects and  inhibited disease progression. Addressing aberrant proteins and lipids may offer a new therapeutic strategy for ALS.