The Dorsal Root Ganglia in Adrenomyeloneuropathy: Neuronal Atrophy and Abnormal Mitochondria

Abstract

Adrenomyeloneuropathy (AMN), a disease of spinal cord, brain, adrenal, and testis, mostly affects men with spastic paraparesis or ataxia beginning in their second or third decade. The spinal cord displays bilateral, usually symmetrical, long tract degeneration particularly of the gracile tract in a "dying-back" pattern. The available data strongly indicate that the fundamental lesion in AMN is an axonopathy or neuronopathy. We compared lumbar dorsal root ganglia (DRG) from 3 AMN patients to 6 age-matched controls histologically, morphometrically, immunohistochemically, and ultrastructurally. There was no apparent neuronal loss, necrosis or apoptosis, nor obvious atrophy; nodules of Nageotte were sparse in both groups. The morphometric studies, however, did reveal neuronal atrophy with a decrease in the number of large neurons and a corresponding increase in neurons less than 2,000 microm2, especially in the 1,500-1,999 microm2 range. No consistent immunohistochemical differences were observed, and no specific cell type appeared to be lost. Many mitochondria in the AMN neurons demonstrated lipidic inclusions; this raises the possibility that, in addition to the well-known peroxisomal defect, impaired mitochondrial function may lead to a failure of ATP-dependent axoplasmic transport in AMN spinal tracts with consequent "dying-back" axonal degeneration. The observation that the DRG parent neurons of the degenerate gracile tracts in AMN undergo atrophy and do not display appreciable evidence of cell death, even at autopsy, provides a wide window of opportunity for the development of therapeutic strategies to combat or prevent this myeloneuropathy.

Role of ALDP (ABCD1) and Mitochondria in X-Linked Adrenoleukodystrophy

“…Saturated long-chain (C 16:0 to C 18:0 ) fatty acids have been shown to be toxic to intestinal mitochondria (21). Most recently, lipidic intramitochondrial inclusions have been observed in atrophic neurons of dorsal root ganglia of patients with adrenomyeloneuropathy, the adult form of X-ALD (29). Lipidic inclusions may be derived from "disintegrating cristae caused by some noxious influence" (13) and have been noted in several mitochondrial disorders (reviewed in reference 29).…”

Absence of Functional Peroxisomes from Mouse CNS Causes Dysmyelination and Axon Degeneration

“…Interestingly, adrenomyeloneuropathy, caused by a defect in the peroxisomal transporter ABCD1, is postulated to be a fundamental defect in the axonal or neuronal membrane, which leads to degeneration but not to apoptotic cell death (Powers et al, 2000(Powers et al, , 2001. Also in a mouse model with ABCD1 deficiency, it was demonstrated that axonal damage occurs as first pathological event followed by myelin degeneration (Pujol et al, 2004).…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…For example, in the dorsal root ganglia of adult X-ALD patients, atrophic neurons were observed with lipidic inclusions in the mitochondria (Powers et al, 2001), and abnormal mitochondria (condensed cristae, myelinoid figures, mitochondrial dissolution) were found in the adrenal cortical cells of (presymptomatic) 12-13 month-old ABCD1-deficient mice (McGuinness et al, 2003). In addition, a defective OXPHOS could be observed in ex vivo spinal cord slices from such mice (López-Erauskin et al, 2013), and signs of ROS (e.g., increased MDE-lysine levels) in this tissue could already be demonstrated as early as 3.5 months of age (Fourcade et al, 2008).…”