Synaptic Changes in the Thalamocortical System of Cathepsin D-Deficient Mice

Abstract

Cathepsin D (CTSD; EC 3.4.23.5) is a lysosomal aspartic protease, the deficiency of which causes early-onset and particularly aggressive forms of neuronal ceroid-lipofuscinosis in infants, sheep, and mice. Cathepsin D deficiencies are characterized by severe neurodegeneration, but the molecular mechanisms behind the neuronal death remain poorly understood. In this study, we have systematically mapped the distribution of neuropathologic changes in CTSD-deficient mouse brains by stereologic, immunologic, and electron microscopic methods. We report highly accentuated neuropathologic changes within the ventral posterior nucleus (ventral posteromedial [VPM]/ventral posterolateral [VPL]) of thalamus and in neuronal laminae IV and VI of the somatosensory cortex (S1BF), which receive and send information to the thalamic VPM/VPL. These changes included pronounced astrocytosis and microglial activation that begin in the VPM/VPL thalamic nucleus of CTSD-deficient mice and are associated with reduced neuronal number and redistribution of presynaptic markers. In addition, loss of synapses, axonal pathology, and aggregation of synaptophysin and synaptobrevin were observed in the VPM/VPL. These synaptic alterations are accompanied by changes in the amount of synaptophysin/synaptobrevin heterodimer, which regulates formation of the SNARE complex at the synapse. Taken together, these data reveal the somatosensory thalamocortical circuitry as a particular focus of pathologic changes and provide the first evidence for synaptic alterations at the molecular and ultrastructural levels in CTSD deficiency.

Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

“…PGRN is therefore likely to be primarily implicated in lysosomal biogenesis that leads to microglial activation and microgliosis. In the present study, we showed that aged PGRNdeficient mice presented with increased accumulation of p62 and ubiquitin in the VPM/VPL, where the main pathological changes have been observed in reported NCL model mice [15][16][17][18]. p62/ubiquitin inclusions have been observed when the autophagy-lysosomal system is disrupted [26].…”

“…These pathological changes in aged PGRN-deficient mice are partially consistent with previous studies [11,13,33], though the brain regions examined were different. Analyses using NCL model mice in the previous studies revealed that glial activation precedes neuronal loss in the VPM/VPL [17,34]. Therefore, the particular vulnerability of the VPM/VPL in PGRN-deficient mice might be attributed to cytotoxicity of glial cells.…”

“…NCL model animals show a particular vulnerability early during disease progression in the sensory thalamocortical pathways, i.e., projections from the ventral posteromedial nucleus/ventral posterolateral nucleus (VPM/VPL) of the thalamus to the primary somatosensory barrelfield cortex (S1BF) [15]. Localized aggregation of activated microglia and astrocytes followed by neuronal cell loss occur in this area [16][17][18]. Impaired myelination also occurs as a feature of some NCL models such as mice deficient in palmitoylprotein thioesterase 1 (Ppt1), ceroid-lipofuscinosis, neuronal 5 (Cln5), and ceroid-lipofuscinosis, neuronal 8 (Cln8) genes [19,20].…”

The neuronal ceroid lipofuscinoses: the same, but different?

“…Over the last decade, we have been characterizing each of the available mouse models of NCL, documenting the onset and progression of pathological changes [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] and testing the efficacy of a range of therapeutic interventions [35][36][37][38]. Our studies have revealed a number of new and surprising pathological features that are broadly shared by the different forms of NCL, but with subtype-specific differences in the staging of these events and some more pronounced differences between certain forms of NCL.…”

Specific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal Dystrophy

“…Synaptic alterations have previously been suggested as initiating events causing NCL in the CLN5-knockout sheep 22 and in a mouse model of lysosomal disease due to a defect in cathepsin D function (CLN10). 23 Overall, the data suggest that macular photoreceptors appear to be most sensitive to mutations in MFSD8. Extramacular photoreceptors are the next most vulnerable, with cortical neurons being the most resistant of the affected cell types.…”