Tauopathy in the young autistic brain: novel biomarker and therapeutic target

Abstract

Given our recent discovery of somatic mutations in autism spectrum disorder (ASD)/intellectual disability (ID) genes in postmortem aged Alzheimer's disease brains correlating with increasing tauopathy, it is important to decipher if tauopathy is underlying brain imaging results of atrophy in ASD/ID children. We concentrated on activity-dependent neuroprotective protein (ADNP), a prevalent autism gene. The unique availability of multiple postmortem brain sections of a 7-year-old male, heterozygous for ADNP de novo mutation c.2244Adup/p.His559Glnfs*3 allowed exploration of tauopathy, reflecting on a general unexplored mechanism. The tested subject exhibited autism, fine motor delays, severe intellectual disability and seizures. The patient died after multiple organ failure following liver transplantation. To compare to other ADNP syndrome mutations, immortalized lymphoblastoid cell lines from three different patients (including ADNP p.Arg216*, p.Lys408Valfs*31, and p.Tyr719* heterozygous dominant mutations) and a control were subjected to RNA-seq. Immunohistochemistry, high-throughput gene expression profiles in numerous postmortem tissues followed. Comparisons to a control brain and to extensive datasets were used. Live cell imaging investigated Tau-microtubule interaction, protecting against tauopathy. Extensive child brain tauopathy paralleled by multiple gene expression changes was discovered. Tauopathy was explained by direct mutation effects on Tau-microtubule interaction and correction by the ADNP active snippet NAP. Significant pathway changes (empirical P value < 0.05) included over 100 genes encompassing neuroactive ligand-receptor and cytokine-cytokine receptor interaction, MAPK and calcium signaling, axon guidance and Wnt signaling pathways. Changes were also seen in steroid biosynthesis genes, suggesting sex differences. Selecting the most affected genes by the ADNP mutations for gene expression analysis, in multiple postmortem tissues, identified Tau (MAPT)-gene-related expression changes compared with extensive normal gene expression (RNA-seq) databases. ADNP showed relatively reduced expression in the ADNP syndrome cerebellum, which was also observed for 25 additional genes (representing >50% of the tested genes), including NLGN1, NLGN2, PAX6, SMARCA4, and SNAP25, converging on nervous system development and tauopathy. NAP provided protection against mutated ADNP disrupted Tau-microtubule association. In conclusion, tauopathy may explain brain-imaging findings in ADNP syndrome children and may provide a new direction for the development of tauopathy protecting drug candidates like NAP in ASD/ID.

Age and Sex-Dependent ADNP Regulation of Muscle Gene Expression Is Correlated with Motor Behavior: Possible Feedback Mechanism with PACAP

“…Foxp1 and the androgen receptor are co-expressed in striatal medium spiny neurons and brain-specific androgen receptor KO (Ar NesCre ) mice exhibit reduced Foxp1 expression in the striatum at E17.5 and P7.5 and an increased Foxp2 level in the cortex at P7.5 [ 58 ]. Our previous bioinformatics results showed ADNP regulation of steroid pathways [ 15 ] and our current results suggest that this may be extended to the specific muscle cells. Furthermore, this steroid regulation may be linked with the higher prevalence of autism in boys compared to girls [ 58 ], with ADNP being a major autism driving gene [ 59 , 60 ].…”

“…In the adult mouse, Adnp regulates hundreds of genes important for brain and immune functions [ 12 , 13 ]. Importantly, there is a significant resemblance between mouse and human ADNP gene regulation [ 13 , 14 , 15 ]. The resemblance is further accentuated by the fact that mouse Adnp mRNA is 90% identical to human ADNP mRNA [ 2 ].…”

Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting

“…It should be mentioned that ADNP plays a dual role, one cytoplasmic with strong microtubule-autophagy-linked activities [ 13 , 15 , 23 , 26 , 27 , 80 ] and one as a transcription factor, chromatin remodeler [ 9 , 16 , 17 ]. Our previous gene array and RNA-seq results did not emphasize the ADNP regulation of the muscle disease genes studied here [ 9 , 25 , 80 ]. Indeed, some regulation may occur, with ADNP interacting with CCCTC-binding factor (CTCF) sites [ 19 ], enriched in many genes [ 81 ].…”

“…As ADNP was linked before to heart development in mice [ 46 ] and in humans [ 5 ], our current data may also imply sex-dependent ADNP effects in adult/aging heart diseases. Most interestingly, we have shown sexual dichotomy in microtubule dynamics also in association with Adnp expression [ 25 ], with ADNP regulating steroid pathways [ 80 ], impinging on sex differences in muscle function.…”

The ADNP Syndrome and CP201 (NAP) Potential and Hope

“…Mice with both Adnp genes deleted (Adnp −/− ) do not survive, as Adnp is critical for neural tube closure and further brain formation (4,23). Most recent data showed direct protection of CP201 against deleterious effects of ADNP pathogenic sequence variants spanning the ADNP protein (24,25) as detailed below.…”